MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'Current Topics in Medicinal Chemistry' source. Thu, 18 Mar 2010 16:16:22 +0100 http://www.medworm.com/index.php?rid=3308733&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20180757%26dopt%3DAbstract This article describes recent advances in the development and biological evaluation of small molecule inhibitors for the serine/threonine kinase Akt (PKB) as a reprise of our 2005 review with new data from the 2006-2009 time period. Akt plays a pivotal role in cell survival and proliferation through a number of downstream effectors. Recent studies indicate that unregulated activation of the PI3K/Akt pathway is a prominent feature of many human cancers and Akt is over-expressed or activated in all major cancers. Akt is considered an attractive target for cancer therapy and inhibition of Akt alone or in combination with standard cancer chemotherapeutics has been postulated to reduce the apoptotic threshold and preferentially kill cancer cells. Recently, several series of small molecule, ATP-... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3308733 Thu, 25 Feb 2010 00:00:00 +0100 3308733 http://www.medworm.com/index.php?rid=3308732&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20180758%26dopt%3DAbstract Authors: Qi LW, Liu EH, Chu C, Peng YB, Li P, Cai HX Diabetes mellitus (DM), the third killer of the mankind health along with cancer, cardiovascular and cerebrovascular diseases, is one of the most challenging diseases facing health care professionals today. The World Health Organization (WHO) has declared that a DM epidemic is underway. Primary DM and its complications are costly to manage, not only for affected individuals, but also for healthcare systems around the world. Screening of anti-diabetic agents has been extensively investigated in the past decades. Natural products (NPs) have served as a major source of drugs for centuries, and about half of the pharmaceuticals in use today are derived from natural substances. Many natural products especially plants-derived medicines hav... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3308732 Thu, 25 Feb 2010 00:00:00 +0100 3308732 http://www.medworm.com/index.php?rid=3308731&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20180759%26dopt%3DAbstract Authors: Liu G SCD1 is a novel target for the treatment of dyslipidemia, obesity, and other symptoms of metabolic syndrome. Extensive target validation has been obtained using SCD1-deficient mice, anti-sense oligonucleotide and RNA interference-mediated knockdown of SCD1, and has supported a controlling role for SCD1 in regulation of lipid biosynthesis and energy expenditure. In this review, the recent advances in small-molecule SCD1 inhibitors will be summarized. The pharmacological and adverse effects of SCD1 inhibitors in relevant rodent models will also be reviewed. The future prospect of SCD1 inhibition in the treatment of metabolic diseases will be discussed. PMID: 20180759 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3308731 Thu, 25 Feb 2010 00:00:00 +0100 3308731 http://www.medworm.com/index.php?rid=3308730&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20180760%26dopt%3DAbstract Authors: Nomura S Plasma glucose is continuously filtered through the glomerulus and then is reabsorbed via the transcellular transport system of proximal tubules in the kidney. The glucose reabsorption system in the kidney is mediated by sodium-dependent glucose cotransporters (SGLTs). Most of filtered glucose is reabsorbed by the low affinity, high capacity SGLT2 located in the proximal renal tubule. SGLT2 inhibitors, such as T-1095, enhance urinary glucose excretion and consequently lower blood glucose levels independent of insulin action. The principle behind SGLT inhibition involves the amelioration of diabetic conditions without increasing body weight and the risk of hypoglycemia. A number of SGLT2 inhibitors are being developed for the treatment of diabetes. This review offers t... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3308730 Thu, 25 Feb 2010 00:00:00 +0100 3308730 http://www.medworm.com/index.php?rid=3308729&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20180761%26dopt%3DAbstract Authors: Yu LF, Qiu BY, Nan FJ, Li J AMPK is a potential target of metabolic diseases including obesity and type 2 diabetes. The activation of AMPK can lead to an increase of glucose uptake into muscle, decreased gluconeogenesis in liver, increased fatty acid oxidation in muscle and liver, decreased fatty acid synthesis in liver and adipose tissue, and increase mitochondrial biogenesis. Until now, many efforts from industrial and academia have been focused on searching novel agents that activate AMPK directly or indirectly. This review will discuss recent advances in the search for novel therapeutic agents that mediate their activity via AMPK activation. PMID: 20180761 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3308729 Thu, 25 Feb 2010 00:00:00 +0100 3308729 http://www.medworm.com/index.php?rid=3308728&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20180762%26dopt%3DAbstract Authors: Zhong M TGR5 (also known as GPBAR1, M-BAR, BG37, hGPCR19, and AXOR 109) is a specific membrane G-protein-coupled receptor (GPCR) of bile acids (BAs). It has recently become an attractive therapeutic target for the prevention and/or the treatment of obesity and its highly associated Type II diabetes and metabolic syndrome. It has also been implicated in many other inflammatory, cardiovascular, neurological, and hepatic diseases. This review briefly describes the biological rationale of TGR5 as an attractive therapeutic target and summarizes some recent efforts on the development of TGR5 modulators. PMID: 20180762 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3308728 Thu, 25 Feb 2010 00:00:00 +0100 3308728 http://www.medworm.com/index.php?rid=3302328&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20170472%26dopt%3DAbstract Authors: Gravius A, Pietraszek M, Dekundy A, Danysz W Since more than one decade, metabotropic glutamate receptors have been under investigation as targets for various CNS disorders such as anxiety, pain, depression, schizpohrenia, Alzheimer's disease and Parkinson's disease. It has been shown that some mGluRs play a crucial role in cognitive processes such as learning and memory, which was initially, demonstrated using knockout mice for each receptor subtype. Later, selective pharmacological tools were developed allowing more specific examinations of the involvement of mGluR1-8 in various forms of learning and memory. Ligands for group I and II mGluRs have been proposed as promising candidates for the treatment of cognitive disorders such as schizophrenia, Fragile X syndrome, Alzheime... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3302328 Thu, 18 Feb 2010 00:00:00 +0100 3302328 http://www.medworm.com/index.php?rid=3291189&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20166942%26dopt%3DAbstract Authors: Stocking EM, Letavic MA, Bonaventure P, Carruthers NI Depression is a major health issue, which is routinely treated with selective serotonin reuptake inhibitors. However, although these agents display a favorable effect on mood, they often fail to improve conditions that accompany depression including cognitive impairment and fatigue. In pre-clinical studies histamine H(3) receptor antagonists have demonstrated both pro-cognitive and wake-promoting effects suggesting that the combination of a histamine H(3) receptor antagonist and a serotonin reuptake inhibitor may have utility as an antidepressant therapy. To this end we sought to introduce histamine H(3) receptor antagonist activity into both known selective serotonin reuptake inhibitors and novel templates. These efforts h... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3291189 Thu, 18 Feb 2010 00:00:00 +0100 3291189 http://www.medworm.com/index.php?rid=3291188&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20166943%26dopt%3DAbstract This article reviews the medicinal implications of 5-HT(4)R in the peripheral and central nervous systems, based on data from two hundred bibliographic references. An exhaustive compilation of molecules reported to be antagonists or agonists for 5-HT(4)R is presented, including chemical structures, binding properties and pharmacological profiles. In the last part of the review, some key concepts concerning structure-activity relationships are highlighted. PMID: 20166943 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3291188 Thu, 18 Feb 2010 00:00:00 +0100 3291188 http://www.medworm.com/index.php?rid=3291187&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20166944%26dopt%3DAbstract Authors: Brea J, Castro-Palomino J, Yeste S, Cubero E, Párraga A, Domínguez E, Loza MI 5-HT(2B) receptors have been reported to play an important role at cardiac, intestinal and central levels, as well as in bone marrow formation and growth. In the last decade, 5-HT(2B) receptors have also gained much attention as new targets in therapeutics, but also as off-targets because their activation along with the inhibition of serotonin transporters plays a significant role in the pathogenesis of 5-HT induced valvulopathy. Taking this into account, the present review focuses on the new therapeutic applications of 5-HT(2B) receptor ligands as well as on the potential concerns. PMID: 20166944 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3291187 Thu, 18 Feb 2010 00:00:00 +0100 3291187 http://www.medworm.com/index.php?rid=3291186&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20166945%26dopt%3DAbstract Authors: Glennon RA, Siripurapu U, Roth BL, Kolanos R, Bondarev ML, Sikazwe D, Lee M, Dukat M Arylsulfonyl analogs of aminopyrimidines (e.g. Ro 04-6790; 2), aminopyridines (e.g. Ro 63-0563; 3), 1-phenylpiperazines (e.g. SB-271046; 4), and tryptamines (e.g. MS-245; 5) were described as the first examples of selective 5-HT(6) receptor antagonists only ten years ago. Today, hundreds of compounds of seemingly diverse structure have been reported. The early antagonists featured an arylsulfonyl group leading to the wide notspread assumption that an arylsulfonyl moiety might be critical for binding and antagonist action. With respect to the arylsulfonyltryptamines, it seems that neither the "arylsulfonyl" nor the "tryptamine" portion of these compounds is essential for binding or for antagoni... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3291186 Thu, 18 Feb 2010 00:00:00 +0100 3291186 http://www.medworm.com/index.php?rid=3291184&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20166946%26dopt%3DAbstract Authors: Volk B, Nagy BJ, Vas S, Kostyalik D, Simig G, Bagdy G Although the 5-HT(5) receptor subfamily was discovered more than 15 years ago, it is unambiguously the least known 5-HT receptor subtype. The G(i)/G(0)-mediated signal transduction and its intensive presence in raphe and other brainstem and pons nuclei suggest mechanisms similar to those of 5-HT(1) receptors, the ligands of which are already applied in the treatment of e.g. anxiety and migraine. In addition, a unique coupling and inhibition of adenosine diphosphate-ribosyl cyclase have also been described. High concentrations of 5-HT(5) receptor in other key regions including, e.g. locus coeruleus, nucleus of the solitary tract, arcuate and suprachiasmatic nuclei of the hypothalamus indicate a wide range of physiological ef... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3291184 Thu, 18 Feb 2010 00:00:00 +0100 3291184 http://www.medworm.com/index.php?rid=3291183&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20166947%26dopt%3DAbstract This article highlights recent advances in the discovery of new agonists, antagonists and partial agonists of the 5-HT(1D) receptor. The field of 5-HT(1D) agonists continues to deliver a number of new potential therapeutic agents, although advances in this field are now more focussed on the clinical evaluation phase. The identification of novel compounds is greater for the 5-HT(1D) receptor antagonists, and whilst few truly selective ligands have been identified, a number of approaches are discussed towards defined mixed-pharmacology profiles. An overview is also given of recent advances in biological and clinical understanding of the receptor. PMID: 20166947 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3291183 Thu, 18 Feb 2010 00:00:00 +0100 3291183 http://www.medworm.com/index.php?rid=3291182&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20166948%26dopt%3DAbstract Authors: Cappelli A, Butini S, Brizzi A, Gemma S, Valenti S, Giuliani G, Anzini M, Mennuni L, Campiani G, Brizzi V, Vomero S The 5-HT(3) receptor (5-HT(3)R) occupies a special place among the serotonin receptor subtypes because it has been shown to be a ligand-gated ion channel, which is involved in a number of physiological functions and important pathologies. 5-HT(3)R antagonists have shown an outstanding efficacy in the control of the emesis induced by anticancer chemotherapy and few adverse side-effects, so as to revolutionize the treatment of nausea in cancer patients. This review covers the authors' work performed during the past decade in the development of 5-HT(3)R ligands belonging to the class of arylpiperazine derivatives related to quipazine (quipazine-like arylpiperazines,... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3291182 Thu, 18 Feb 2010 00:00:00 +0100 3291182 http://www.medworm.com/index.php?rid=3291181&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20166949%26dopt%3DAbstract Authors: Ludewig S, Kossner M, Schiller M, Baumann K, Schirmeister T Fluorimetric assays are convenient and efficient to determine the inhibitory potency of enzyme inhibitors. Since enzyme activity can be blocked in a number of ways, it is important to determine the exact mode of inhibition. The first part of the review deals with kinetic methods to distinguish among the different modes of inhibition. In addition to that, pitfalls are discussed that can be encountered if the mode of inhibition was not thoroughly investigated. The second part of the review deals with some basic techniques of hit validation. Specifically, three error sources that may result in misleadingly strong inhibitors are scrutinized and exemplified for two different typical protease assays (cathepsin B, chymotryps... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3291181 Thu, 18 Feb 2010 00:00:00 +0100 3291181 http://www.medworm.com/index.php?rid=3291180&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20166950%26dopt%3DAbstract Authors: Wegscheid-Gerlach C, Gerber HD, Diederich WE Malaria, caused by protozoa of the genus Plasmodium, remains one of the most dreadful infectious diseases worldwide killing more than 1 million people per year. The emergence of multidrug-resistant parasites highly demands a steadfast and continuous search not only for new targets but also for new anti-infectives addressing the known ones. As proteases in general have been proven to be excellent drug targets and the development of inhibitors has frequently resulted in approved drugs, this review will only focus on the proteases of Plasmodium falciparum as drug targets. The completion of the sequencing of the Plasmodium falciparum genome in 2002 lead to the discovery of nearly 100 putative proteases encoded therein. Within this revie... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3291180 Thu, 18 Feb 2010 00:00:00 +0100 3291180 http://www.medworm.com/index.php?rid=3291179&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20166951%26dopt%3DAbstract Authors: Steuber H, Hilgenfeld R The occurrence of life-threatening viral infections and the establishment of appropriate defense strategies exhibit major challenges to the disease management in our society. The unpredictable character of viral outbreaks will even be enhanced in the future due to human activities such as increasing international travel, deforestation, changes in social conditions, or influences induced by the climate change. The defense against these pathogenic agents requires preparedness, including successful drug design strategies. Viral proteases represent attractive targets for the design of anti-infective lead compounds, as in case that a viral mRNA encoding several types of proteins is recognized as a monocistronic template by the host-cell translation machinery... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3291179 Thu, 18 Feb 2010 00:00:00 +0100 3291179 http://www.medworm.com/index.php?rid=3291178&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20166952%26dopt%3DAbstract Authors: Frizler M, Stirnberg M, Sisay MT, Gütschow M It is now becoming clear that several papain-like cysteine cathepsins are involved in the pathophysiology of diseases such as osteoporosis, autoimmune disorders, and cancer. Therefore, the development of potent and selective cathepsin inhibitors is an attractive subject for medicinal chemists. New advances have been made for nitrile-based inhibitors, leading to the identification of the cathepsin K inhibitor odanacatib and other candidates with potential for therapeutic use. This review summarizes the development of peptidic and peptidomimetic compounds with an electrophilic nitrile 'warhead' as inhibitors of the cysteine cathepsins B, S, L, C, and K. Peptide nitriles have been shown to reversibly react with the active site cys... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3291178 Thu, 18 Feb 2010 00:00:00 +0100 3291178 http://www.medworm.com/index.php?rid=3291177&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20166953%26dopt%3DAbstract Authors: Pietsch M, Chua KC, Abell AD The physiological roles of calpains are discussed, as are the associated pathological disorders that result from their over-activation. We also present practical information for establishing functional inhibition assays and an overview of X-ray crystal structures of calpain-inhibitor complexes to aid inhibitor design. These structures reveal the expected extended beta-strand conformation for the inhibitor backbone, a geometry that has been engineered into inhibitors with the introduction of either an N-terminal heterocycle or a macrocycle that links the P(1) and P(3) residues. The structure and function of all the main classes of inhibitors are reviewed, with most examples being classified according to the nature of the C-terminal reactive warhead ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3291177 Thu, 18 Feb 2010 00:00:00 +0100 3291177 http://www.medworm.com/index.php?rid=3291176&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20166954%26dopt%3DAbstract Authors: Straub A, Roehrig S, Hillisch A Several clinical candidates have now emerged as a result of an intense search for orally available, antithrombotic factor Xa inhibitors. This review highlights the discovery of XareltoTM (Rivaroxaban) starting from an initial tetrahydrophthalimide screening hit. The major breakthrough was the finding that a chlorothiophene moiety can undergo an interaction in the S1 binding site thus leading to high potency combined with favorable oral bioavailability. The binding mode of this P1 moiety is discussed, and further non-basic S1 binders of this new type are reviewed. PMID: 20166954 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3291176 Thu, 18 Feb 2010 00:00:00 +0100 3291176 http://www.medworm.com/index.php?rid=3291175&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20166955%26dopt%3DAbstract Authors: Genin E, Reboud-Ravaux M, Vidal J The search for proteasome inhibitors began fifteen years ago. These inhibitors proved to be powerful tools for investigating many important cellular processes regulated by the ubiquitin-proteasome pathway. Targeting the proteasome pathway can also lead to new treatments for disorders like cancer, muscular dystrophies, inflammation and immune diseases. This is already true for cancer; the FDA approved bortezomib, a potent proteasome inhibitor, for treating multiple myeloma in 2003, and mantle cell lymphoma in 2006. The chemical structures identified in some of the early proteasome inhibitors have led to the development of new anti-cancer drugs (CEP-18770, Carfilzomib, NPI-0052). All these molecules are covalent bonding inhibitors that react wit... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3291175 Thu, 18 Feb 2010 00:00:00 +0100 3291175 http://www.medworm.com/index.php?rid=3291174&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20166956%26dopt%3DAbstract Authors: Wolkenberg SE, Sur C The simple amino acid glycine is implicated in both inhibitory and excitatory neurotransmission in mammalian central nervous system, and it modulates excitatory neurotransmission through its role as a necessary co-agonist for glutamatergic N-methyl-D-aspartate (NMDA) receptors. Given the involvement of NMDA receptor-mediated neurotransmission in complex cerebral processes such as cognition, pharmacological manipulation of extracellular synaptic glycine biology is an active area of pharmaceutical research to develop novel treatments for neuropsychiatric disorders. A key component of cerebral glycine metabolism is the glycine transporter type 1 (GlyT1) and elevation of extracellular synaptic glycine concentration by blockade of GlyT1 has been hypothesized to... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3291174 Thu, 18 Feb 2010 00:00:00 +0100 3291174 http://www.medworm.com/index.php?rid=3291173&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20166957%26dopt%3DAbstract Authors: Schmidt CJ As might be predicted for an organ designed for cell to cell communication, cyclic nucleotide signaling in the brain is highly organized and regulated. Augmentation of cyclic nucleotide signaling by means of phosphodiesterase inhibition appears to be a viable and tractable means of enhancing neuronal communication. Of the various CNS disorders that have been considered as target indications for phosphodiesterase inhibitors, no condition has received more attention than cognitive dysfunction. This review provides a background for understanding the expanding literature in this field as well as a brief update on the rationale driving the search for selective inhibitors of targets such as PDE1B, PDE2, PDE5 and PDE9. PMID: 20166957 [PubMed - as supplied by publisher]... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3291173 Thu, 18 Feb 2010 00:00:00 +0100 3291173 http://www.medworm.com/index.php?rid=3291172&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20166958%26dopt%3DAbstract Authors: Rossé G, Schaffhauser H Cognitive impairment (CI) has been recognized as a core feature of Alzheimer's disease (AD) and schizophrenia. The 5-HT(6) receptor is an attractive target for the development of cognitive enhancers due to its unique localization and pharmacology. 5-HT(6) receptor antagonists have been shown to modulate multiple neurotransmitter systems and therefore enhance cognition in preclinical studies. This premise translated into the clinical efficacy of the 5-HT(6) receptor antagonist SB-742457 in mild-to-moderate AD patients. Advances in the understanding of the structure-activity-relationship, the design of novel 5-HT(6) receptor ligands and their potential application for the treatment of CI are reviewed. PMID: 20166958 [PubMed - as supplied by publi... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3291172 Thu, 18 Feb 2010 00:00:00 +0100 3291172 http://www.medworm.com/index.php?rid=3291171&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20166959%26dopt%3DAbstract Authors: Haydar SN, Dunlop J Nicotinic acetylcholine receptors (nAChR) have been strongly implicated as therapeutic targets for treating cognitive deficits in disorders such as schizophrenia and Alzheimer's disease (AD). In particular alpha7 and alpha4beta2 subtype-selective nAChR agonists and partial agonists have been developed as potential candidates for the treatment of schizophrenia, cognitive disorders (including Alzheimer's disease), and inflammation. Further development of positive allosteric modulators and antagonists were also recently reported in the literature. In this review we will cover recent developments focused on the above mentioned nAChR subtypes, starting from the most advanced clinical candidate followed by an overview of literature compounds where potency, select... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3291171 Thu, 18 Feb 2010 00:00:00 +0100 3291171 http://www.medworm.com/index.php?rid=3291170&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20166960%26dopt%3DAbstract Authors: Raddatz R, Tao M, Hudkins RL The H(3) histamine receptor is expressed in many brain regions, including those involved in sleep/wake regulation and cognitive functions. Inhibition of the H(3) receptor leads to increased release of multiple neurotransmitters in these regions, making this receptor an ideal target for the potential enhancement of arousal and/or cognitive processes. The high interest level by several pharmaceutical companies in H(3) receptors as potential drug targets has produced rapid advancement in novel compound series with different properties, providing a variety of preclinical tools as well as advancing several candidates into clinical trials. Multiple chemotypes have demonstrated efficacy in preclinical models covering a range of cognitive deficits, suggest... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3291170 Thu, 18 Feb 2010 00:00:00 +0100 3291170 http://www.medworm.com/index.php?rid=3036369&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19939219%26dopt%3DAbstract Authors: Fang WS, Fang JZ PMID: 19939219 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3036369 Sun, 29 Nov 2009 06:52:02 +0100 3036369 http://www.medworm.com/index.php?rid=3031185&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19929849%26dopt%3DAbstract Authors: Fang WS, Fang JZ PMID: 19929849 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3031185 Fri, 27 Nov 2009 10:22:03 +0100 3031185 http://www.medworm.com/index.php?rid=3031201&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19929824%26dopt%3DAbstract Authors: Talele TT, Khedkar SA, Rigby AC Drug discovery and development is an interdisciplinary, expensive and time-consuming process. Scientific advancements during the past two decades have changed the way pharmaceutical research generate novel bioactive molecules. Advances in computational techniques and in parallel hardware support have enabled in silico methods, and in particular structure-based drug design method, to speed up new target selection through the identification of hits to the optimization of lead compounds in the drug discovery process. This review is focused on the clinical status of experimental drugs that were discovered and/or optimized using computer-aided drug design. We have provided a historical account detailing the development of 12 small molecules (Captopri... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3031201 Mon, 23 Nov 2009 00:00:00 +0100 3031201 http://www.medworm.com/index.php?rid=3031200&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19929825%26dopt%3DAbstract Authors: Khakar PS With the dawn of new century, major technological advances in the drug discovery field have revolutionized absorption, distribution, metabolism, excretion and toxicity (ADME/T) profiling of new chemical entities (NCEs) among others. The progress made in the in vitro experimental determination of the ADME/T properties fueled the growth in the so-called predictive ADME/T. The process of in silico model development improved significantly with the availability of high quality data as well newer, more accurate statistical methods of analysis. Even several such models appear in the literature regularly, the prediction accuracy is limited to 'local' rather than 'global' applicability domain in majority of the cases. Majority of the efforts are still needed to address severa... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3031200 Mon, 23 Nov 2009 00:00:00 +0100 3031200 http://www.medworm.com/index.php?rid=3031199&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19929826%26dopt%3DAbstract Authors: Verma J, Khedkar VM, Coutinho EC Quantitative structure-activity relationships (QSAR) have been applied for decades in the development of relationships between physicochemical properties of chemical substances and their biological activities to obtain a reliable statistical model for prediction of the activities of new chemical entities. The fundamental principle underlying the formalism is that the difference in structural properties is responsible for the variations in biological activities of the compounds. In the classical QSAR studies, affinities of ligands to their binding sites, inhibition constants, rate constants, and other biological end points, with atomic, group or molecular properties such as lipophilicity, polarizability, electronic and steric properties (Hansch ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3031199 Mon, 23 Nov 2009 00:00:00 +0100 3031199 http://www.medworm.com/index.php?rid=3031198&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19929827%26dopt%3DAbstract Authors: Menikarachchi LC, Gascón JA One of the goals of medicinal chemistry concerns the ability to compute protein-ligand interactions based on the structural knowledge of the receptor. To this end, the majority of current approaches incorporate classical force field potentials to describe receptor-ligand interactions. One of the most critical problems of standard molecular mechanics (MM) force fields is their fixed-charge treatment of electrostatic interactions. Two problems are derived from this approximation, polarization and charge transfer. As an immediate step in computational complexity, it seems natural to incorporate Quantum Mechanics (QM) within a hybrid QM/MM approach, which has shown to be a useful tool to describe structural and mechanistic aspects of chromophores a... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3031198 Mon, 23 Nov 2009 00:00:00 +0100 3031198 http://www.medworm.com/index.php?rid=3031197&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19929828%26dopt%3DAbstract Authors: Sarkar A, Kellogg GE Hydrophobic interactions are some of the most important interactions in nature. They are the primary driving force in a number of phenomena. This is mostly an entropic effect and can account for a number of biophysical events such as protein-protein or protein-ligand binding that are of immense importance in drug design. The earliest studies on this phenomenon can be dated back to the end of the 19(th) century when Meyer and Overton independently correlated the hydrophobic nature of gases to their anesthetic potency. Since then, significant progress has been made in this realm of science. This review briefly traces the history of hydrophobicity research along with the theoretical estimation of partition coefficients. Finally, the application of hydrophobic... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3031197 Mon, 23 Nov 2009 00:00:00 +0100 3031197 http://www.medworm.com/index.php?rid=3031196&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19929829%26dopt%3DAbstract Authors: Daga PR, Patel RY, Doerksen RJ Protein modeling has been a very challenging problem in drug discovery and computational biology. The latest advances and progress in computational power have helped to solve this problem to a considerable extent; however, predicting accurate three-dimensional structure of proteins has always been and remains a complicated assignment. Of the two common methods of protein structure prediction, template-based modeling has become more popular than ab initio modeling. In this review, we summarize the developments in methodology and of understanding for comparative protein modeling during the last three years, including for homologue search, fold recognition, secondary structure prediction, model building, loop building, side-chain prediction and mode... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3031196 Mon, 23 Nov 2009 00:00:00 +0100 3031196 http://www.medworm.com/index.php?rid=3031195&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19929830%26dopt%3DAbstract Authors: de Beer SB, Vermeulen NP, Oostenbrink C Although water molecules are small and only consist of two different atom types, they play various roles in cellular systems. This review discusses their influence on the binding process between biomacromolecular targets and small molecule ligands and how this influence can be modeled in computational drug design approaches. Both the structure and the thermodynamics of active site waters will be discussed as these influence the binding process significantly. Structurally conserved waters cannot always be determined experimentally and if observed, it is not clear if they will be replaced upon ligand binding, even if sufficient space is available. Methods to predict the presence of water in protein-ligand complexes will be reviewed. Subseq... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3031195 Mon, 23 Nov 2009 00:00:00 +0100 3031195 http://www.medworm.com/index.php?rid=3031194&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19929831%26dopt%3DAbstract Authors: Zhou T, Huang D, Caflisch A Quantum mechanical (QM) methods are becoming popular in computational drug design and development mainly because high accuracy is required to estimate (relative) binding affinities. For low-to medium-throughput in silico screening, (e.g., scoring and prioritizing a series of inhibitors sharing the same molecular scaffold) efficient approximations have been developed in the past decade, like linear scaling QM in which the computation time scales almost linearly with the number of basis functions. Furthermore, QM-based procedures have been used recently for determining protonation states of ionizable groups, evaluating energies, and optimizing molecular structures. For high-throughput in silico screening QM approaches have been employed to derive robu... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3031194 Mon, 23 Nov 2009 00:00:00 +0100 3031194 http://www.medworm.com/index.php?rid=3031193&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19929832%26dopt%3DAbstract We present a review of various fragment-based discovery and de novo design protocols with an emphasis on successful applications in real-world drug discovery projects. Furthermore, we illustrate the strengths and weaknesses of the various approaches and discuss how one method can be used to complement another. We also discuss how the incorporation of experimental data as constraints in computational models can produce novel compounds that occupy unique areas in intellectual property (IP) space yet are biased toward the desired chemical property space. Finally, we present recent research results suggesting that computational tools applied to fragment-based discovery and de novo design can have a greater impact on the discovery process when coupled with the right experiments. PMID: 19929... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3031193 Mon, 23 Nov 2009 00:00:00 +0100 3031193 http://www.medworm.com/index.php?rid=3031192&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19929833%26dopt%3DAbstract Authors: Amaro RE, Li WW Ensemble based virtual screening refers to the use of conformational ensembles from crystal structures, NMR studies or molecular dynamics simulations. It has gained greater acceptance as advances in the theoretical framework, computational algorithms, and software packages enable simulations at longer time scales. Here we focus on the use of computationally generated conformational ensembles and emerging methods that use these ensembles for discovery, such as the Relaxed Complex Scheme or Dynamic Pharmacophore Model. We also discuss the more rigorous physics-based computational techniques such as accelerated molecular dynamics and thermodynamic integration and their applications in improving conformational sampling or the ranking of virtual screening hits. Fina... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3031192 Mon, 23 Nov 2009 00:00:00 +0100 3031192 http://www.medworm.com/index.php?rid=3031191&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19929834%26dopt%3DAbstract Authors: Nienaber V Diseases of the central nervous system are among the most devastating to patients and their families. Despite this, treatments for these diseases have lagged behind other therapeutic areas. Although social and economic factors may be partly responsible for the paucity of therapeutic agents, a particularly daunting challenge for CNS drug discovery is the need for compounds to cross the blood brain barrier. Recent analyses of successful drugs have shown that their chemical properties have not changed substantially over the past 40 years while the properties of compounds entering the clinic have become inflated. This property inflation has only exacerbated the challenges of CNS drug discovery as the requirements for delivery to the brain are even more stringent than th... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3031191 Mon, 23 Nov 2009 00:00:00 +0100 3031191 http://www.medworm.com/index.php?rid=3031190&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19929835%26dopt%3DAbstract Authors: Verlinde CL, Fan E, Shibata S, Zhang Z, Sun Z, Deng W, Ross J, Kim J, Xiao L, Arakaki TL, Bosch J, Caruthers JM, Larson ET, Letrong I, Napuli A, Kelly A, Mueller N, Zucker F, Van Voorhis WC, Merritt EA, Hol WG The history of fragment-based drug discovery, with an emphasis on crystallographic methods, is sketched, illuminating various contributions, including our own, which preceded the industrial development of the method. Subsequently, the creation of the BMSC fragment cocktails library is described. The BMSC collection currently comprises 68 cocktails of 10 compounds that are shape-wise diverse. The utility of these cocktails for initiating lead discovery in structure-based drug design has been explored by soaking numerous protein crystals obtained by our MSGPP (Medical Stru... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3031190 Mon, 23 Nov 2009 00:00:00 +0100 3031190 http://www.medworm.com/index.php?rid=3031189&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19929836%26dopt%3DAbstract Authors: Siegal G, Hollander JG Using localized NMR spectroscopy on immobilized targets provides us with a method to simultaneously assess binding of small molecules to two different samples. This Target Immobilized NMR Screening (TINS) has a number of advantages, not least is the requirement for minimal quantities of non-isotopically labeled protein and the applicability to insoluble or unstable targets. The technique is sensitive to binding with K(D) values in the range of 100 nM to 20 mM, while careful selection of the reference protein reduces the number of false positive hits. This combination ensures a maximal number of valid hits from which to select starting points for hit elaboration projects. Hits can be prioritized using biological assays when appropriate, as well as an arra... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3031189 Mon, 23 Nov 2009 00:00:00 +0100 3031189 http://www.medworm.com/index.php?rid=3031188&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19929837%26dopt%3DAbstract Authors: Reitz AB, Smith GR, Tounge BA, Reynolds CH Fragment-based drug discovery (FBDD) is an important new tool to understand the molecule basis of ligand-biological target interactions. By combining optimal fragments, it is often possible to construct larger molecular weight compounds that have greater potency in a shorter period of time than can been achieved by the initial screening of larger molecular weight compound libraries. Alternatively, if screening of more traditional larger libraries has occurred, then it may be possible to analyze the data during the process of hit triage in such as way as to essentially adopt a fragment-based approach in reverse. In this review, we highlight general principles associated with the efficiency indices such as Ligand Efficiency (LE) in whic... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3031188 Mon, 23 Nov 2009 00:00:00 +0100 3031188 http://www.medworm.com/index.php?rid=3031187&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19929838%26dopt%3DAbstract Authors: Danielson UH The transition from high throughput screening of collections of drug-like compounds to screening of fragment libraries via lower throughput methods with high sensitivity has revolutionized early drug discovery. It is highlighting the need for sensitive biophysical techniques for interaction analysis rather than high throughput methods. Biosensors with SPR detection are well suited for this novel scenario. In less than 20 years the technique has been launched, established and become a highly informative method for a variety of applications in drug discovery. It is no longer limited to the detection of proteins or other high molecular weight analytes, but the detection of weakly interacting fragments is now feasible. This paper discusses the theoretical and experime... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3031187 Mon, 23 Nov 2009 00:00:00 +0100 3031187 http://www.medworm.com/index.php?rid=3031186&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19929839%26dopt%3DAbstract Authors: Davies TG, Woodhead SJ, Collins I Multiple ligand efficient fragment inhibitors of protein kinase B were identified through a combined in silico compound screen and high-throughput crystallographic analysis of protein-ligand structures. A well-validated apo-PKB-PKA chimeric protein provided a convenient platform for high-throughput crystallography by soaking of inhibitors, and a method for the determination of PKB-ligand structures was developed to support inhibitor development. Pyrazole and azaindole fragment hits with micromolar activity were rapidly progressed to nanomolar inhibitors of PKB with activity in cells using crystallographic analysis of inhibitor binding modes to guide medicinal chemistry. Compounds with selectivity for PKB over PKA and other kinases were identif... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3031186 Mon, 23 Nov 2009 00:00:00 +0100 3031186 http://www.medworm.com/index.php?rid=3015589&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19925434%26dopt%3DAbstract Authors: Huryn DM PMID: 19925434 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3015589 Sat, 21 Nov 2009 20:58:02 +0100 3015589 http://www.medworm.com/index.php?rid=3015588&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19925435%26dopt%3DAbstract Authors: Tuttolomondo A PMID: 19925435 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3015588 Sat, 21 Nov 2009 20:58:02 +0100 3015588 http://www.medworm.com/index.php?rid=3015587&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19925436%26dopt%3DAbstract Authors: Blagg BS PMID: 19925436 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=3015587 Sat, 21 Nov 2009 20:58:02 +0100 3015587 http://www.medworm.com/index.php?rid=2983212&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19903156%26dopt%3DAbstract Authors: Wang Q, Li YF, Chang JB Lignans are widely distributed in nature. The earliest recorded medicinal use of lignans dated back to over 1000 years ago. Lignan-rich plant products were also active ingredients in Chinese and Japanese folk medicines for the treatment of various diseases. The dried root and stem of this plant are listed in the Chinese pharmacopoeia for the treatment of rheumatoid arthritis, gastric, duodenal ulcers and many other diseases. This review highlights synthetic strategies for the Wuweizisu C analogs and the important pharmacological activities as well as therapeutic findings related to the treatment of HBV and other diseases. Notably a significant and ongoing project on Wuweizisu C and its analogs has led to the discovery and development of two potent deriv... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2983212 Wed, 11 Nov 2009 00:00:00 +0100 2983212 http://www.medworm.com/index.php?rid=2983211&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19903157%26dopt%3DAbstract Authors: Chen Q Nordihydroguaiaretic acid is a natural occurring lignan mainly isolated and commercially produced from desert plant, creosote bush (Larrea divaricata Cav. Or Corillea tridentate), which can be widely found in the border zone of southern of USA and northern of Mexico. During past 100 years, extensive research has demonstrated that nordihydroguaiaretic acid and its synthetic analogues are potentially useful in treating diseases related to cancers, diabetes, viral, bacterial infections, and inflammation. Remarkably, terameprocol, a tetra-O-methyl derivative of nordihydroguaiaretic acid, is currently in Phase I/II clinical trials as an anticancer agent. This review deals with the chemical synthesis and bioactivities of nordihydroguaiaretic acid and its structurally-related ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2983211 Wed, 11 Nov 2009 00:00:00 +0100 2983211 http://www.medworm.com/index.php?rid=2983210&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19903158%26dopt%3DAbstract Authors: Dai J Over 200 derivatives have been obtained through chemo-enzymatic transformation of the taxanes derived from cell cultures of Taxus chinensis. The reversal activity towards MDR tumor cells and cyto-toxicity of most these compounds were evaluated, and several derivatives exhibited powerful MDR reversal activity. The substrate-specificities of the two most important biotransformation reactions-C-7beta and 9alpha hydroxylations, were investigated and preliminarily concluded. In addition, some key intermediates in hypothetically biosynthetic pathway of taxoid were obtained. These results indicate that biotransformation combined with chemical transformation is a powerful approach to structural diversification of natural products, lead compound discovery and the study on the str... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2983210 Wed, 11 Nov 2009 00:00:00 +0100 2983210 http://www.medworm.com/index.php?rid=2983209&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19903159%26dopt%3DAbstract Authors: Kulka M The impact of natural products on human health has been enormous, and the study of natural products continues to influence research in the fields of chemistry, biology, and ecology. Historically, the majority of our medicines originate from natural products and their synthetic derivatives, many of which have taught us valuable lessons about biology. While advances in synthetic and combinatorial chemistry have given rise to notable successes in the development of new drugs, the perceived value of natural products in the treatment of allergic disease has yet to be fully explored. The immune system is a highly complex, intricately regulated group of cells whose integrated function is essential to health. Cells of the immune system may interact in a cell-cell manner and ma... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2983209 Wed, 11 Nov 2009 00:00:00 +0100 2983209 http://www.medworm.com/index.php?rid=2983207&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19903160%26dopt%3DAbstract Authors: Zhan J Aromatic polyketides represent important members of the family of polyketides, which have displayed a wide assortment of bioactive properties, such as antibacterial, antitumor, and antiviral activities. Bacterial aromatic polyketides are mainly synthesized by type II polyketide synthases (PKSs). Whereas malonyl-CoA is exclusively used as the extender unit, starter units can vary in different aromatic polyketide biosynthetic pathways, leading to a variety of polyketide backbones. Once the polyketide chains are elongated by the minimal PKSs to the full length, the immediate tailoring enzymes including ketoreductases, oxygenases and cyclases will work on the nascent chains to form aromatic structures, which will be further decorated by those late tailoring enzymes such as ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2983207 Wed, 11 Nov 2009 00:00:00 +0100 2983207 http://www.medworm.com/index.php?rid=2983205&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19903161%26dopt%3DAbstract Authors: Wang SR, Fang WS Pentacyclic triterpenoids exert their antitumor activity through different mechanisms, one of which is apoptosis induction. Although there are many reports on the apoptosis inducing activity of pentacyclic triterpenoids, a systematic survey and discussion on their structure-activity relationships (SARs) is still lacking. In this review, we summarized such activity of oleanane, ursane and lupane type triterpenoids, the most abundant pentacyclic triterpene prototypes in plants. Their structural characteristics responsible for the activity are also discussed, in order to unravel their SARs for the apoptotic induction and benefit further investigations on the antitumor triterpenoids. PMID: 19903161 [PubMed - as supplied by publisher] (Source: Current Topics in... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2983205 Wed, 11 Nov 2009 00:00:00 +0100 2983205 http://www.medworm.com/index.php?rid=2983204&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19903162%26dopt%3DAbstract Authors: Acuña UM, Jancovski N, Kennelly EJ Many new polyisoprenylated benzophenones with a bicyclo[3.3.1]-nonane-2,4,9-trione core structure have been isolated from plants in the Clusiaceae family, and their potent biological properties have been the subject of several studies. This review summarizes the biological activities reported for these secondary metabolites including cytotoxic, antimicrobial, antioxidant, and anti-inflammatory activities. Our efforts during the past years have foremost been directed towards isolating new polyisoprenylated benzophenones, as well as understanding the possible target and mechanism of action through which these compounds arrest cancer cells and inhibit the progression of the cell-cycle. The transcription of genes is affected in cancer cells ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2983204 Wed, 11 Nov 2009 00:00:00 +0100 2983204 http://www.medworm.com/index.php?rid=2983202&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19903163%26dopt%3DAbstract Authors: Yin H, Du Y, Zhang J Chitosan is one of the most abundant marine-based biopolymers. Low molecular weight and oligomeric chitosans are water-soluble hydrolysates of chitosan. They have been shown to have a wide range of biological activities and industrial applications. In particular, low molecular weight and oligomeric chitosans have been reported to have the health benefits such as immunity regulation, anti-tumor, liver protection, blood lipids lowering, anti-diabetic, antioxidant and anti-obesity. In this paper, the preparation and analytical methods, and bioactivities of these low molecular weight and oligomeric chitosans were reviewed, with the latest progresses introduced and discussed. PMID: 19903163 [PubMed - as supplied by publisher] (Source: Current Topics in Medi... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2983202 Wed, 11 Nov 2009 00:00:00 +0100 2983202 http://www.medworm.com/index.php?rid=2983201&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19903164%26dopt%3DAbstract Authors: Chakraborty C, Hsu CH, Wen ZH, Lin CS The chemical and biological diversity of the different marine evolutionary group is endless and therefore, this is an amazing resource for the discovery of new anticancer drugs. Comprising 34 of the 36 Phyla of life, marine ecosystems are indeed our last genetic diversity and biotechnological boundary; terrestrial systems possess only 17 Phyla. Sponges, coelenterates and microorganisms are the foremost resources of therapeutic compounds. Algae, echinoderms, tunicates, mollusks, bryozoans are also the sources of anticancer drugs from marine resources. We highlight the past and current status of marine anticancer pharmacology using different marine groups. PMID: 19903164 [PubMed - as supplied by publisher] (Source: Current Topics in Medi... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2983201 Wed, 11 Nov 2009 00:00:00 +0100 2983201 http://www.medworm.com/index.php?rid=2983200&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19903165%26dopt%3DAbstract Authors: Li X, Guo J, Dai S, Ouyang Y, Wu H, Sun W, Wang G Microorganisms of millions species exist in every corner of the Earth, and form a dynamic genetic reservoir that are not clearly revealed and categorized due to barrier in current cultivation technology. Their applications in biomedical and environmental aspects are more than satisfactory. However, the situation has drastically changed during the turn of the century because of the rapid development of phylogenetic studies based on rRNA sequencing independent of standard laboratory cultivation. More recently, high throughput sequencing technology which enables direct sequencing of community DNA for metagenomic analyses are making a direct impact on our understanding of microbial diversity, ecology, and secondary metabolism. In t... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2983200 Wed, 11 Nov 2009 00:00:00 +0100 2983200 http://www.medworm.com/index.php?rid=2983199&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19903166%26dopt%3DAbstract Authors: Ghosh N, Sheldrake HM, Searcey M, Pors K CC-1065, the duocarmycins and yatakemycin are members of a family of ultrapotent antitumour antibiotics that have been the subject of extensive investigations due to their mode of action and potential in the design of new anticancer therapeutics. The natural products and their analogues exert their effects through a sequence selective alkylation of duplex DNA in the minor groove at the N3 of adenine. An understanding of their structure and its effect on biological activity has been derived through chemical synthesis and has also generated new potential lead compounds. These studies form the first section of the review. The desire to progress these compounds to clinic has also led to studies of bioconjugation and prodrug formation and th... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2983199 Wed, 11 Nov 2009 00:00:00 +0100 2983199 http://www.medworm.com/index.php?rid=2942997&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860704%26dopt%3DAbstract Authors: Reitz AB PMID: 19860704 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942997 Fri, 30 Oct 2009 15:50:06 +0100 2942997 http://www.medworm.com/index.php?rid=2942994&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860705%26dopt%3DAbstract This article discusses research results and events surrounding the discovery and development of topiramate. PMID: 19860705 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942994 Fri, 30 Oct 2009 15:50:06 +0100 2942994 http://www.medworm.com/index.php?rid=2942991&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860706%26dopt%3DAbstract Authors: Morris K, McAlpine S PMID: 19860706 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942991 Fri, 30 Oct 2009 15:50:06 +0100 2942991 http://www.medworm.com/index.php?rid=2942990&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860707%26dopt%3DAbstract Authors: Barichievy S, Saayman S, Arbuthnot P, Weinberg MS The naturally-occurring RNA interference (RNAi) pathway represents a powerful tool for the sequence-specific post-transcriptional silencing of gene expression. By exploiting the endogenous mammalian RNAi pathway, several expression-based strategies have been developed to inhibit human immunodeficiency virus (HIV) gene expression and replication. This approach potentially has utility as a protective 'therapeutic vaccine' of virus-susceptible lymphocytes. In this review we discuss new developments aimed at improving efficacy and delivery of novel RNAi-based gene expression antiviral strategies. Particular attention is given to advances in combinatorial gene expression systems that prevent the emergence of RNAi-resistant virus by ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942990 Fri, 30 Oct 2009 15:50:06 +0100 2942990 http://www.medworm.com/index.php?rid=2942989&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860708%26dopt%3DAbstract Authors: Suzuki K, Kelleher AD Small RNA molecules, including small interfering RNA (siRNA) and micro RNA (miRNA), have rapidly emerged as important regulators of gene expression. Recent articles have demonstrated RNA mediated complex induced transcriptional gene silencing (TGS) occurring in the nucleus. Originally the small RNA mediated TGS pathway has been reported in yeast and plants, currently a number of articles strongly suggest that this newly established gene silencing mechanism is present in mammals. RNA mediated TGS has been reported for various human promoters including inhibition of tumor susceptibility genes, X-chromosome inactivation and suppression of human chemokine receptor. Small RNAs can inhibit human viral infection through the TGS pathway. Prolonged HIV-1 transcrip... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942989 Fri, 30 Oct 2009 15:50:06 +0100 2942989 http://www.medworm.com/index.php?rid=2942988&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860709%26dopt%3DAbstract Authors: Jafari M, Chen P Applying RNA interference to silence a specific gene has opened a new and promising avenue of gene therapy. But a key bottleneck is the poor stability and inability of naked siRNA to translocate through cell membranes. Among several delivery systems, cationic peptides capable of penetrating cell membranes have drawn attention due to their structural and functional versatility, potential biocompatibility and ability to target cells. In this review, different classes of peptides employed in siRNA delivery are reviewed. In particular, a new class of siRNA delivery peptides with high transfection efficiency and low cytotoxicity is introduced. PMID: 19860709 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942988 Fri, 30 Oct 2009 15:50:06 +0100 2942988 http://www.medworm.com/index.php?rid=2942987&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860710%26dopt%3DAbstract Authors: Okuda T, Kawaguchi Y, Okamoto H RNA interference (RNAi) is an attractive phenomenon for practical use that specifically inhibits gene expression and is carried out by small double-stranded RNAs (dsRNAs) including small interfering RNA (siRNA) or short hairpin RNA (shRNA). In addition, RNAi is of great interest for clinical use to cure refractory diseases related to the expression of a specific gene. To achieve gene silencing in the body, a sufficient amount of dsRNA must be delivered and internalized into target cells. However, dsRNAs have a large molecular weight and net negative charge, which limits their membrane-permeating ability. Moreover, dsRNAs are rapidly degraded by endonucleses in the body. Therefore, for the efficient delivery of dsRNAs, many approaches based on dr... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942987 Fri, 30 Oct 2009 15:50:06 +0100 2942987 http://www.medworm.com/index.php?rid=2942986&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860711%26dopt%3DAbstract Authors: Detzer A, Sczakiel G The efficient delivery of biologically functional short interfering RNA (siRNA) in vivo remains a widely unresolved technical problem in therapeutic drug development. The repertoire of concepts for the cellular uptake of oligonucleotide-based tools and drugs has been extended by the mechanistically novel finding that phosphorothioate (PS)-modified single-stranded oligodeoxyribonucleotides (ON) promote the intracellular accumulation of naked extra-cellular siRNA in a variety of cell types. This mode of delivery gives rise to substantial intracellular amounts of siRNA, up to 10(4) siRNA molecules per cell. Conversely, the moderate biological effectiveness strongly indicates that intracellular release of siRNA from sub-cellular compartments where it seems to ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942986 Fri, 30 Oct 2009 15:50:06 +0100 2942986 http://www.medworm.com/index.php?rid=2942985&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860712%26dopt%3DAbstract Authors: Morin A, Gallou-Kabani C, Mathieu JR, Cabon F Synthetic small interfering RNAs (siRNAs) open promising new therapeutic perspectives in acute and chronic pathologies. A number of experiments in mice demonstrated the ability of naked siRNAs injected under a normal pressure to trigger gene silencing in vivo, translating into a measurable phenotype. We focus in this review on the information that we can gain from these experiments, and discuss how the specificity of the gene silencing in vivo can be controlled. Because the activity of most drugs increases with the dosing, we are prone to consider that increasing the concentration of siRNAs within cells enhances the efficiency and the duration of the silencing. However, because RNAi is a saturable process, and because increasing th... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942985 Fri, 30 Oct 2009 15:50:06 +0100 2942985 http://www.medworm.com/index.php?rid=2942984&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860713%26dopt%3DAbstract Authors: Liu YP, Berkhout B RNA interference (RNAi) holds great promise as gene therapy approach against viral pathogens, including HIV-1. A specific anti-HIV-1 response can be induced via transfection of synthetic small interfering RNAs (siRNAs) or via intracellular transgene expression of short hairpin RNAs (shRNAs) or microRNAs (miRNAs). Both targeting of the viral mRNAs or the mRNAs for cellular co-factors that are required for viral replication have been shown successful in suppressing HIV-1 replication. However, like conventional mono-therapies, the use of a single anti-HIV-1 RNAi inducer results in the emergence of RNAi-escape mutants. To prevent viral escape, a combinatorial RNAi approach should be used in which multiple RNAi effectors against HIV-1 are simultaneously expressed... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942984 Fri, 30 Oct 2009 15:50:06 +0100 2942984 http://www.medworm.com/index.php?rid=2942983&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860714%26dopt%3DAbstract Authors: Zhou J, Rossi JJ Aptamers that are evolved by the SELEX procedure (Systematic Evolution of Ligands by Exponential enrichment) can specifically recognize and tightly bind their cognate targets by means of well-defined secondary and three-dimensional structures. In comparison to antibodies, nucleic acid-based aptamers offer some exciting advantages, including the potential for chemical synthesis, convenient modification, chemical versatility, stability and lack of immunogenicity. During the past 20 years, aptamers have been developed for various applications such as diagnostics, drug development, target validation and therapeutics. Aptamers targeting cell surface proteins are being explored as promising delivery vehicles to target a distinct disease or tissue in a cell-type-spec... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942983 Fri, 30 Oct 2009 15:50:06 +0100 2942983 http://www.medworm.com/index.php?rid=2942982&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860729%26dopt%3DAbstract Authors: Matts RL, Manjarrez JR The Hsp90-dependence of many oncogenic proteins has precipitated a great deal of interest in Hsp90 as a drug target, as evidence mounts that Hsp90 inhibitors may be effective chemotherapeutic agents for the treatment of cancer. In addition, Hsp90-inhibitors have shown promise for the treatment of neurodegenerative diseases characterized by the accumulation of toxic denatured protein aggregates. The development of assays for the identification of novel Hsp90 inhibitors began in earnest when it became apparent that the Hsp90 inhibitors available at the time had less than ideal pharmacological properties. This review summarizes what is known about Hsp90's structure and function, its ATPase cycle, its interactions with co-chaperones and clients, and the effe... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942982 Wed, 28 Oct 2009 00:00:00 +0100 2942982 http://www.medworm.com/index.php?rid=2942981&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860730%26dopt%3DAbstract Authors: Kim YS, Alarcon SV, Lee S, Lee MJ, Giaccone G, Neckers L, Trepel JB Twenty-five years ago the first small molecule inhibitors of Hsp90 were identified. In the intervening years there has been dramatic progress in basic scientific understanding of the Hsp90 chaperone machinery and in the role of Hsp90 in malignancy. The first-in-class Hsp90 inhibitor 17-AAG entered into Phase I clinical trials in 1999. There are now 13 Hsp90 inhibitors in clinical trial, representing multiple drug classes, and hundreds of patients have been treated in adult oncology and pediatric oncology trials. This review will provide an overview of the clinical trial results thus far. In addition, pivotal issues in further development of Hsp90 inhibitors as anticancer drugs will be discussed. PMID: 1986... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942981 Wed, 28 Oct 2009 00:00:00 +0100 2942981 http://www.medworm.com/index.php?rid=2942980&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860731%26dopt%3DAbstract Authors: Brandt GE, Blagg BS The 90 kDa heat shock protein (Hsp90) has become a validated target for the development of anti-cancer agents. Several Hsp90 inhibitors are currently under clinical trial investigation for the treatment of cancer. All of these agents inhibit Hsp90's protein folding activity by binding to the N-terminal ATP binding site of the Hsp90 molecular chaperone. Administration of these investigational drugs elicits induction of the heat shock response, or the overexpression of several Hsps, which exhibit antiapoptotic and pro-survival effects that may complicate the application of these inhibitors. To circumvent this issue, alternate mechanisms for Hsp90 inhibition that do not elicit the heat shock response have been identified and pursued. After providing background... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942980 Wed, 28 Oct 2009 00:00:00 +0100 2942980 http://www.medworm.com/index.php?rid=2942979&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860732%26dopt%3DAbstract Authors: Taldone T, Chiosis G Hsp90 is a molecular chaperone with important roles in regulating the function of several proteins with potential pathogenic activity. Because many of these proteins are involved in cancer and neurodegenerative promoting pathways, Hsp90 has emerged as an attractive therapeutic target in these diseases. Molecules that bind to the N-terminal nucleotide pocket of Hsp90 inhibit its activity, and consequently, disrupt client protein function. A number of these inhibitors from several chemical classes are now known, and some are already in clinical trials. This review focuses on the purine class of Hsp90 inhibitors, their discovery through rational design, and on efforts aimed towards their optimization and development into clinically viable drugs for the treatm... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942979 Wed, 28 Oct 2009 00:00:00 +0100 2942979 http://www.medworm.com/index.php?rid=2942978&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860733%26dopt%3DAbstract Authors: Winssinger N, Fontaine JG, Barluenga S Heat shock protein 90 (Hsp90) is an ATP-dependent chaperone which is involved in the post-translational maturation and stabilization of over one hundred proteins ("its clients"). In the absence of Hsp90's chaperoning, its clients are misfolded and degraded via ubiquitin-proteasome pathway. It has become the focus of intense drug discovery efforts as its activity has been implicated in diverse pathologies ranging from oncology to neurodegenerative and infectious diseases. The most promising inhibitors reported to date inhibit the ATPase activity by binding to the N-terminal ATP pocket. Radicicol, a member of the resorcylic acid lactones (RALs), represents an important pharmacophore to this end. Efforts towards the development of this pharm... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942978 Wed, 28 Oct 2009 00:00:00 +0100 2942978 http://www.medworm.com/index.php?rid=2942977&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860734%26dopt%3DAbstract Authors: Porter JR, Ge J, Lee J, Normant E, West K The ansamycin class of natural products is well known for its anti-tumor effects and has been extensively studied by cancer researchers for nearly four decades. The first description of geldanamycin in the scientific literature appeared in 1970 and nearly thirty years later the semi-synthetic derivative 17-AAG, or tanespimycin, entered Phase 1 clinical trials. In the subsequent years, three additional geldanamycin derivatives have entered clinical evaluation. Kosan Biosciences developed 17-DMAG or alvespimycin hydrochloride for clinical evaluation as both an intravenous and oral product. Infinity Pharmaceuticals is developing IPI-504 or retaspimycin hydrochloride as an intravenous product, which is in several Phase 2 clinical trials; I... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942977 Wed, 28 Oct 2009 00:00:00 +0100 2942977 http://www.medworm.com/index.php?rid=2942976&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860735%26dopt%3DAbstract Authors: Verkhivker GM, Dixit A, Morra G, Colombo G The molecular chaperone Hsp90 (90 kDa heat-shock protein) mediates many fundamental cellular pathways involved in cell proliferation, cell survival, and cellular stress response. Hsp90 is responsible for the correct conformational development, stability and function in crowded cell environments. Structural and computational biology studies have recently provided important insights into underlying molecular mechanisms of Hsp90 function. These developments have revealed a critical role of Hsp90 structure, conformational dynamics and interdomain communication in promoting the binding and release of ligands and its interaction with client proteins. By disabling multiple signal transduction pathways, Hsp90 inhibition provides a powerful th... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942976 Wed, 28 Oct 2009 00:00:00 +0100 2942976 http://www.medworm.com/index.php?rid=2942975&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860736%26dopt%3DAbstract Authors: Prodromou C Hsp90 is involved in the maturation and activation of client proteins. Often these are key proteins involved in signal transduction and regulatory pathways that in a mutated and/or deregulated form sustain an oncogenic cellular state. Consequently, the malignancy is maintained with the aid of Hsp90 upon which the mutated proteins have become particularly dependent for their activity. The requirement for the Hsp90 chaperone machine to drive the malignancy makes Hsp90 a prime anticancer target, an 'axle in a wheel' that when disrupted has been shown to be effective in killing cancerous cells. This review aims to identify potential drug targets, based on the current structural knowledge of the Hsp90-chaperone machine, that could be targeted with the aim of disrupting ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942975 Wed, 28 Oct 2009 00:00:00 +0100 2942975 http://www.medworm.com/index.php?rid=2942974&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19860737%26dopt%3DAbstract Authors: Patury S, Miyata Y, Gestwicki JE The molecular chaperone, heat shock protein 70 (Hsp70), acts at multiple steps in a protein's life cycle, including during the processes of folding, trafficking, remodeling and degradation. To accomplish these various tasks, the activity of Hsp70 is shaped by a host of co-chaperones, which bind to the core chaperone and influence its functions. Genetic studies have strongly linked Hsp70 and its co-chaperones to numerous diseases, including cancer, neurodegeneration and microbial pathogenesis, yet the potential of this chaperone as a therapeutic target remains largely underexplored. Here, we review the current state of Hsp70 as a drug target, with a special emphasis on the important challenges and opportunities imposed by its co-chaperones, prot... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2942974 Wed, 28 Oct 2009 00:00:00 +0100 2942974 http://www.medworm.com/index.php?rid=2923908&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19849659%26dopt%3DAbstract Authors: Tuttolomondo A, Di Sciacca R, Di Raimondo D, Arnao V, Renda C, Pinto A, Licata G Involvement of various neurotransmitters and neuromodulators have been shown to contribute to the ischemic injury and neuronal death associated with stroke Role of excitatory amino acid receptor activation, calcium overload, nitric oxide, and oxidative stress in the pathogenesis of ischemic brain damage is well established. Several new strategies are currently emerging, based on recent advances in our understanding of molecular pathways that could be considered as potential therapeutic targets. For example reactive oxygen species (ROS) are important contributors to the secondary injury cascade following traumatic brain injury (TBI), and ROS inhibition has consistently been shown to be neuroprotect... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2923908 Thu, 22 Oct 2009 00:00:00 +0100 2923908 http://www.medworm.com/index.php?rid=2923907&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19849660%26dopt%3DAbstract In this study there was a significant 14% proportional reduction in mortality during the scheduled treatment period (343 [3.3%] deaths among aspirin-allocated patients vs 398 [3.9%] deaths among placebo-allocated patients; 2p = 0.04). There were significantly fewer recurrent ischaemic strokes in the aspirin-allocated than in the placebo-allocated group (167 [1.6%] vs 215 [2.1%]; 2p = 0.01) but slightly more haemorrhagic strokes (115 [1.1%] vs 93 [0.9%]. Few studies examined the role of ticlopidin in acute stroke setting the results showed treatment with ticlopidine improved the neurologic outcome. In the Examining the Safety of Loading of Aspirin and Clopidogrel in Acute Ischemic Stroke and TIA (LOAD) study, 40 consecutive ischemic stroke patients were treated with 325 mg of aspirin and 37... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2923907 Thu, 22 Oct 2009 00:00:00 +0100 2923907 http://www.medworm.com/index.php?rid=2923906&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19849661%26dopt%3DAbstract Authors: Tziomalos K, Athyros VG, Karagiannis A, Mikhailidis DP Ischemic stroke is a major cause of morbidity and mortality. Whereas dyslipidemia is a major risk factor for coronary heart disease (CHD), its role in the pathogenesis of ischemic stroke is less clear. Epidemiological studies have provided conflicting findings regarding the association of dyslipidemia with ischemic stroke. Overall, elevated LDL-C levels appear to increase the risk of ischemic stroke. Low HDL-C levels also appear to be associated with a greater risk whereas the importance of high triglyceride levels is less clear. The discordant results of observational studies might result from the heterogeneity of stroke, since dyslipidemia is less likely to play a major role in the pathogenesis of some ischemic stroke su... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2923906 Thu, 22 Oct 2009 00:00:00 +0100 2923906 http://www.medworm.com/index.php?rid=2923905&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19849662%26dopt%3DAbstract Authors: Uyttenboogaart M, De Keyser J, Luijckx GJ In the last decennium, thrombolytic therapy has changed the management of acute ischemic stroke. Randomized clinical studies have demonstrated that intravenous thrombolysis with tissue plasminogen activator improves functional outcomes. Recently the time window for intravenous thrombolysis has been extended from 3 to 4.5 hours after stroke onset, which will allow more stroke patients to benefit from this treatment. Currently several studies are investigating how to improve recanalization rates of thrombolytic therapy. In this review several aspects of intravenous and intra-arterial thrombolysis are discussed. PMID: 19849662 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2923905 Thu, 22 Oct 2009 00:00:00 +0100 2923905 http://www.medworm.com/index.php?rid=2923904&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19849663%26dopt%3DAbstract Authors: Armario P, de la Sierra A Stroke, as a clinical manifestation of the cardiovascular diseases, is one of the leading causes of death and disability in both developed and developing countries. Hypertension is by far, the most important risk factor for stroke. Epidemiological data indicate that the risk of stroke increases with both systolic and diastolic blood pressure elevation, from levels of 115/75 mmHg. It is also evident that most adults worldwide have values above these limits, thus emphasizing the importance of blood pressure as a risk factor for stroke. Clinical trials of antihypertensive treatment, both in studies that have compared active drugs against placebo or in those comparing different types of drugs have clearly demonstrated a protective effect of blood pressure... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2923904 Thu, 22 Oct 2009 00:00:00 +0100 2923904 http://www.medworm.com/index.php?rid=2923903&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19849664%26dopt%3DAbstract Authors: Guyomard V, Jamieson EI, Myint PK Ischaemic stroke is extremely common in western societies contributing to 70-85% of strokes, one of the leading causes of mortality and long-term disability. Despite advancement in preventive measures, the total number of strokes is set to rise in the future due to increasing numbers of aging populations across the world. Diabetes as a risk factor for stroke has been well established. There are also emerging evidence to suggest glucose level management in acute stroke phase as a therapeutic target may be beneficial, albeit remains controversial. One of the issues in difficulty in interpreting study findings is their heterogeneity. In this article, we provide epidemiological, basic science, clinical observational and trial evidence leading to t... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2923903 Thu, 22 Oct 2009 00:00:00 +0100 2923903 http://www.medworm.com/index.php?rid=2923902&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19849665%26dopt%3DAbstract Authors: Tuttolomondo A, Di Sciacca R, Di Raimondo D, Renda C, Pinto A, Licata G Animal models of focal ischaemia induced by middle cerebral artery occlusion (MCAO) provide most evidence for cellular inflammatory responses in stroke. Permanent MCAO results in a modest neutrophil infiltration at 24 h after ischaemia, predominantly around arterial vessels at the margins of infarction, whereas MCAO with subsequent reperfusion is associated with substantial infiltration by neutrophils throughout the entire infarct. Several studies show that C-reactive protein (CRP), an inflammatory marker, is associated with stroke outcomes and future vascular events. Several drugs, especially hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), have been demonstrated to reduce hsCRP levels ind... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2923902 Thu, 22 Oct 2009 00:00:00 +0100 2923902 http://www.medworm.com/index.php?rid=2877060&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19807662%26dopt%3DAbstract Authors: Arterburn JB, Oprea TI, Prossnitz ER, Edwards BS, Sklar LA Recent technological advances in flow cytometry provide a versatile platform for high throughput screening of compound libraries coupled with high-content biological testing and drug discovery. The G protein-coupled receptors (GPCRs) constitute the largest class of signaling molecules in the human genome with frequent roles in disease pathogenesis, yet many examples of orphan receptors with unknown ligands remain. The complex biology and potential for drug discovery within this class provide strong incentives for chemical biology approaches seeking to develop small molecule probes to facilitate elucidation of mechanistic pathways and enable specific manipulation of the activity of individual receptors. We have initiate... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2877060 Tue, 06 Oct 2009 23:00:00 +0100 2877060 http://www.medworm.com/index.php?rid=2877059&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19807663%26dopt%3DAbstract Authors: Wipf P, Arnold D, Carter K, Dong S, Johnston PA, Sharlow E, Lazo JS, Huryn D The Polo-like kinase (Plk) family comprises four cell cycle serine/threonine kinases, Plk1-4. Among these, Plk1 has been most thoroughly characterized; it contains a conserved kinase domain and a C-terminal docking site for S/T-phosphorylated proteins (polo-box domain, PBD). Polo-like kinases are deregulated in oncogenesis and therefore constitute a therapeutic target for cancer. A high throughput screening campaign was carried out by the Pittsburgh Molecular Library Screening Center (PMLSC), using a fluorescence polarization assay with recombinant Plk1-PBD to monitor the inhibition of binding of an optimal phosphopeptide substrate motif with recombinant Plk1-PBD. Screening of 97,090 small molecule li... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2877059 Tue, 06 Oct 2009 23:00:00 +0100 2877059 http://www.medworm.com/index.php?rid=2877058&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19807664%26dopt%3DAbstract Authors: Thomas CJ, Auld DS, Huang R, Huang W, Jadhav A, Johnson RL, Leister W, Maloney DJ, Marugan JJ, Michael S, Simeonov A, Southall N, Xia M, Zheng W, Inglese J, Austin CP The NIH Chemical Genomics Center (NCGC) was the inaugural center of the Molecular Libraries and Screening Center Network (MLSCN). Along with the nine other research centers of the MLSCN, the NCGC was established with a primary goal of bringing industrial technology and experience to empower the scientific community with small molecule compounds for use in their research. We intend this review to serve as 1) an introduction to the NCGC standard operating procedures, 2) an overview of several of the lessons learned during the pilot phase and 3) a review of several of the innovative discoveries reported during the p... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2877058 Tue, 06 Oct 2009 23:00:00 +0100 2877058 http://www.medworm.com/index.php?rid=2877057&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19807665%26dopt%3DAbstract Authors: Xie Y, Rinderspacher A, Liu Y, Gong G, Smith DH, Wyler M, Brandén L, Deng SX Nuclear factor kappa B (NF-kappaB) is an important transcription factor. Aberrant regulation of the NF-kappaB pathway is frequently observed in a number of major ailments such as cancer and inflammatory diseases. Hence NF-kappaB modulators have been intensely pursued for their potential therapeutic applications. Numerous reviews have described recent progress in the development of these agents. More recently, a variety of structurally and functionally novel small molecules, identified through high-throughput screens conducted within the Molecular Libraries Screening Center Network (MLSCN) of the NIH Roadmap for Medical Research, have been added to the current list of NF-kappaB regulators. This re... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2877057 Tue, 06 Oct 2009 23:00:00 +0100 2877057 http://www.medworm.com/index.php?rid=2877056&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19807666%26dopt%3DAbstract We describe our approach for hit validation, characterization and triage that led to a critical understanding of the nature of hits from the cathepsin B project. In addition, we detail our experience at hit identification and optimization that led to the development of a novel thiocarbazate probe of cathepsin L. PMID: 19807666 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2877056 Tue, 06 Oct 2009 23:00:00 +0100 2877056 http://www.medworm.com/index.php?rid=2877055&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19807667%26dopt%3DAbstract This article describes the discovery and development of the first highly selective, small molecule antagonist of the muscarinic acetylcholine receptor subtype I (mAChR1 or M(1)). An M(1) functional, cell-based calcium-mobilization assay identified three distinct chemical series with initial selectivity for M(1) versus M(4). An iterative parallel synthesis approach was employed to optimize all three series in parallel, which led to the development of novel microwave-assisted chemistry and provided important take home lessons for probe development projects. Ultimately, this effort produced VU0255035, a potent (IC(50) = 130 nM) and selective (>75-fold vs. M(2)-M(5) and > 10 microM vs. a panel of 75 GPCRs, ion channels and transporters) small molecule M(1) antagonist. Further profiling d... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2877055 Tue, 06 Oct 2009 23:00:00 +0100 2877055 http://www.medworm.com/index.php?rid=2877054&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19807668%26dopt%3DAbstract Authors: Thepchatri P, Min J, Ganesh T, Du Y, Lewis I, Kurtkaya S, Prussia A, Li L, Plemper RK, Fu H, Liotta DC, Snyder JP, Dingledine R, Sun A A variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads and to accelerate the development of drug candidates. The Emory Chemical and Biology Discovery Center (ECBDC) has been an active participant in the NIH's high-throughput screening (HTS) endeavor to identify potent small molecule probes for poorly studied proteins. Several of Emory's projects relate to cancer or virus infection. We have chosen three successful examples including discovery of potent measles virus RNA-dependent RNA polymerase inhibitors, development of Heat Shock Protein 90 (Hsp90) blockers and identification of angiogenesis... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2877054 Tue, 06 Oct 2009 23:00:00 +0100 2877054 http://www.medworm.com/index.php?rid=2804645&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19754392%26dopt%3DAbstract Authors: Andricopulo AD PMID: 19754392 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2804645 Fri, 18 Sep 2009 01:44:03 +0100 2804645 http://www.medworm.com/index.php?rid=2804644&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19754393%26dopt%3DAbstract Authors: Kolb P, Irwi JJ Whereas docking screens have emerged as the most practical way to use protein structure for ligand discovery, an inconsistent track record raises questions about how well docking actually works. In its favor, a growing number of publications report the successful discovery of new ligands, often supported by experimental affinity data and controls for artifacts. Few reports, however, actually test the underlying structural hypotheses that docking makes. To be successful and not just lucky, prospective docking must not only rank a true ligand among the top scoring compounds, it must also correctly orient the ligand so the score it receives is biophysically sound. If the correct binding pose is not predicted, a skeptic might well infer that the discovery was seren... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2804644 Fri, 18 Sep 2009 01:44:03 +0100 2804644 http://www.medworm.com/index.php?rid=2804643&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19754394%26dopt%3DAbstract Authors: Andricopulo AD, Salum LB, Abraham DJ A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the development of high quality drug candidates. Structure-based drug design (SBDD) methods are becoming increasingly powerful, versatile and more widely used. This review summarizes current developments in structure-based virtual screening and receptor-based pharmacophores, highlighting achievements as well as challenges, along with the value of structure-based lead optimization, with emphasis on recent examples of successful applications for the identification of novel active compounds. PMID: 19754394 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2804643 Fri, 18 Sep 2009 01:44:03 +0100 2804643 http://www.medworm.com/index.php?rid=2804642&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19754395%26dopt%3DAbstract Authors: Clark RD As drug discovery and development has grown ever riskier and more expensive, interest has increased in using computational tools to identify good candidates more quickly and to avoid investing resources in synthesizing and testing compounds that are not likely to succeed. The most powerful of these tools seek to exploit the connection between the three-dimensional (3D) structure of a molecule and its various biological activities. Two fundamentally different ways of addressing this challenge have arisen over the years: ligand-based methods that seek to identify and exploit similarities between the structures of ligands that are known to bind to a given target; and target-based (docking) methods that seek to identify and exploit complementarities to the binding site it... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2804642 Fri, 18 Sep 2009 01:44:03 +0100 2804642 http://www.medworm.com/index.php?rid=2804641&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19754396%26dopt%3DAbstract Authors: Figueroa-Villar JD, Tinoco LW NMR is one of the most powerful techniques for ligand-biomolecule interaction studies and drug screening and design. There are several methods that are strongly used, including chemical shift perturbation (CSP), saturation transfer difference (STD) and diffusion coefficients. However, one of the most useful and easy to apply NMR parameters in medicinal chemistry studies is the spin-lattice relaxation data, which can be employed to investigate the strength and topology of intermolecular interactions, such as drug-drug, drug-protein, drug-DNA, drug-micelle (or vesicle) and biomolecule-biomolecule interactions. This review deals with the newest applications of T(1) in different studies of interest for drug design and evaluation. PMID: 19754396 [P... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2804641 Fri, 18 Sep 2009 01:44:03 +0100 2804641 http://www.medworm.com/index.php?rid=2804640&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19754397%26dopt%3DAbstract Authors: Guido RV, Oliva G Parasitic diseases are amongst the foremost threats to human health and welfare around the world. In tropical and subtropical regions of the world, the consequences of parasitic infections are devastating both in terms of human morbidity and mortality. The current available drugs are limited, ineffective, and require long treatment regimens. To overcome these limitations, the identification of new macromolecular targets and small-molecule modulators is of utmost importance. The advances in genomics and proteomics have prompted drug discovery to move toward more rational strategies. The increasing understanding of the fundamental principles of protein-ligand interactions combined with the availability of compound libraries has facilitated the identification of... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2804640 Fri, 18 Sep 2009 01:44:03 +0100 2804640 http://www.medworm.com/index.php?rid=2804639&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19754398%26dopt%3DAbstract Authors: Cornell W, Nam K Steroid nuclear hormone binding receptors (SHRs) are ligand activated transcription factors involved in the regulation of target genes associated with key physiological and developmental processes. As such they are important targets for drug discovery. Crystal structures are now available for all members of the SHR family, however, earlier studies carried out using homology models proved to be quite valuable for understanding the binding of natural ligands and for designing novel therapeutic agents. The maleability of the binding pocket means that the crystal structure of an SHR in complex with one ligand may not suffice to explain the binding interactions of that same target with a different ligand. Consequently, induced fit docking and molecular dynamics are... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2804639 Fri, 18 Sep 2009 01:44:03 +0100 2804639 http://www.medworm.com/index.php?rid=2804638&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19754399%26dopt%3DAbstract Authors: Dinges J PMID: 19754399 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2804638 Fri, 18 Sep 2009 01:44:03 +0100 2804638 http://www.medworm.com/index.php?rid=2804637&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19754400%26dopt%3DAbstract Authors: Mena MA, Casarejos MJ, Solano RM, de Yébenes JG L-DOPA is a di-hydroxy-phenyl, catecholamine precursor, amino acid, initially considered as an inert compound and now the key stone for the treatment of Parkinson's disease (PD) and some hereditary dystonias. L-DOPA, when administered to mammals, is rapidly metabolized to dopamine and 3-OM-DOPA, and its half-life in plasma is roughly 2 hours which has been considered the explanation for some of the L-DOPA related complications in PD. There have been, therefore, sophisticated methods of improving its pharmacokinetics by the association of decarboxylase and COMT inhibitors, slow release preparations and continuous infusions. In addition to its symptomatic effects, the impact of L-DOPA on the natural course of the disease is in... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2804637 Fri, 18 Sep 2009 01:44:03 +0100 2804637 http://www.medworm.com/index.php?rid=2804636&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19754401%26dopt%3DAbstract Authors: Li J, Dani JA, Le W Parkinson's disease (PD) is characterized by the selective loss of dopamine (DA) neurons in the substantia nigra compacta (SNc). The transcription factor Pitx3 is important for the differentiation and maintenance of midbrain DA neurons during development. There is highly restricted and constitutive expression of Pitx3 in the SNc and ventral tegmental area (VTA) of the midbrain after birth. In addition to its importance during development, Pitx3 also has roles in the long-term survival and maintenance of the midbrain DA neurons. In this review, we discuss the function of Pitx3 throughout the life of midbrain neurons and the contribution of Pitx3 to disease mechanisms. PMID: 19754401 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2804636 Fri, 18 Sep 2009 01:44:03 +0100 2804636 http://www.medworm.com/index.php?rid=2804635&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19754402%26dopt%3DAbstract Authors: Gallagher DA, Schapira AH Parkinson's disease (PD) is a complex neurodegenerative disorder characterised by dopaminergic cell loss in the substantia nigra. In addition, neurodegeneration occurs at a number of extra-nigral locations and involves a variety of non-dopaminergic neurotransmitter systems. Etiopathogenic mechanisms leading to cell death include oxidative stress and free radical generation, mitochondrial dysfunction, glutamate receptor mediated excitotoxicity, inflammation, oligodendrocytic interaction and neurotrophic factors, ubiquitin-proteosome system involvement, autophagy and apoptosis. Each of these is a potential target for novel pharmacotherapies including bioenergetic agents, inhibitors of excitotoxicity, neurotrophic factors, proteosomal enhancers and anti-... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2804635 Fri, 18 Sep 2009 01:44:03 +0100 2804635 http://www.medworm.com/index.php?rid=2804634&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19754403%26dopt%3DAbstract Authors: Isidoro C, Biagioni F, Giorgi FS, Fulceri F, Paparelli A, Fornai F Autophagy is the mechanism through which cells degrade oxidized membranes-organelles and mis/unfolded proteins, in this latter function cooperating with the ubiquitin-proteasome system (UP system). Although autophagy has been known for a long time, its involvement in the pathogenesis of neurodegenerative diseases has been investigated only recently. The most fascinating data are very recent and show an impressive connection between proteins that are mutated in different forms of familial Parkinson's Disease (PD) and the critical role that these proteins play in the physiology of the Autophagy (ATG) pathway. This evidence is supported by neuropathological data showing at the ultrastructural level, the occurrence... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2804634 Fri, 18 Sep 2009 01:44:03 +0100 2804634 http://www.medworm.com/index.php?rid=2804633&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19754404%26dopt%3DAbstract Authors: Biagioni F, Pellegrini A, Ruggieri S, Murri L, Paparelli A, Fornai F The intermittent oral intake of the dopamine (DA) precursor L-3,4-dihydroxyphenylalanine (L-DOPA) is the classic therapy of Parkinson's disease (PD). In this way, the drug precursor can be metabolised into the active neurotransmitter DA. Although this occurs throughout the brain, the therapeutic relief is believed to be due to restoring extracellular DA levels within the dorsal striatum (more in the putamen than the caudate nucleus) which lacks endogenous DA as a consequence of the disease process. However, differing from physiological DA transmission, this therapeutic pattern leads to abnormal peaks of non-synaptic DA, which are supposed to trigger behavioural sensitisation expressed as abnormal involuntary ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2804633 Fri, 18 Sep 2009 01:44:03 +0100 2804633 http://www.medworm.com/index.php?rid=2804632&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19754405%26dopt%3DAbstract Authors: Leverenz JB, Quinn JF, Zabetian C, Zhang J, Montine KS, Montine TJ Parkinson disease (PD) is an already prevalent neurodegenerative disease that is poised to at least double over the next 25 years. Although best known for its characteristic movement disorder, PD is now appreciated commonly to cause cognitive impairment, including dementia, and behavioral changes. Dementia in patients with PD is consequential and has been associated with reduced quality of life, shortened survival, and increased caregiver distress. Here we review clinical presentation and progression, pathological bases, identification of genetic risk factors, development of small molecule biomarkers, and emerging treatments for cognitive impairment in patients with PD. PMID: 19754405 [PubMed - in process] ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2804632 Fri, 18 Sep 2009 01:44:03 +0100 2804632 http://www.medworm.com/index.php?rid=2804631&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19754406%26dopt%3DAbstract Authors: Di Napoli M Idiopathic Parkinson's Disease (PD) is a progressive neurodegenerative disease characterized by dopaminergic neuronal loss within the substantia nigra. The degeneration of dopamine and other neuronal populations in PD lead to both chronic motor and non-motor disabilities but the mechanisms remain unclear. Molecular genetic studies in familial forms of the disease identified key proteins involved in PD pathogenesis, supporting a major role for (i) protein aggregation and neurotoxic alpha-synuclein oligomeric species due to an altered protein quality control, (ii) parkin-driven deregulation of the ubiquitin-proteasome system, (iii) oxidative stress and mithocondrial dysfunction, and, finally, (iv) disturbed kinase activity. The elucidation of these new molecular path... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2804631 Fri, 18 Sep 2009 01:44:03 +0100 2804631 http://www.medworm.com/index.php?rid=2804630&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19754407%26dopt%3DAbstract This article describes recent advances in the development and biological evaluation of small molecule mGluR4 positive allosteric modulators (PAMs), and, to a lesser extent, orthosteric agonists. Due to its expression in the basal ganglia, the Family 3 GPCR metabotropic glutamate receptor subtype 4 (mGluR4) has recently garnered a great deal of attention as a putative target for the treatment of Parkinson's disease and a variety of other CNS disorders. Until 2008, with the exception of the prototypical mGluR4 PAM (-)-PHCCC, very few small molecule tools existed to probe the role of selective activation of mGluR4. This review will focus on the explosion of novel mGluR4 PAMs reported in the past year and the further preclinical validation of mGluR4 activation as a potentially groundbreaking t... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2804630 Fri, 18 Sep 2009 01:44:03 +0100 2804630 http://www.medworm.com/index.php?rid=2797197&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19747119%26dopt%3DAbstract Authors: Drlica K, Hiasa H, Kerns R, Malik M, Mustaev A, Zhao X The quinolones trap DNA gyrase and DNA topoisomerase IV on DNA as complexes in which the DNA is broken but constrained by protein. Early studies suggested that drug binding occurs largely along helix-4 of the GyrA (gyrase) and ParC (topoisomerase IV) proteins. However, recent X-ray crystallography shows drug intercalating between the -1 and +1 nucleotides of cut DNA, with only one end of the drug extending to helix-4. These two models may reflect distinct structural steps in complex formation. A consequence of drug-enzyme-DNA complex formation is reversible inhibition of DNA replication; cell death arises from subsequent events in which bacterial chromosomes are fragmented through two poorly understood pathways. In one pat... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2797197 Sat, 12 Sep 2009 23:00:00 +0100 2797197 http://www.medworm.com/index.php?rid=2797196&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19747120%26dopt%3DAbstract Authors: Caldwell GW, Yan Z, Tang W, Dasgupta M, Hasting B Integrating physicochemical, drug metabolism, pharmacokinetics, ADME, and toxicity assays into drug discovery in order to reduce the attrition rates in clinical development is reviewed. The review is organized around three main decision points used in discovery including hit generation, lead optimization and final candidate selection stages. The preclinical strategies used at each decision point are discussed from a drug discovery perspective. Typically, preclinical data produced at these stages use lower throughput assays, smaller amounts of compounds and operate within a timeframe that is consistent with the iterative cycle of most drug discovery research projects. Understanding the false positive rates of these drug discover... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2797196 Sat, 12 Sep 2009 23:00:00 +0100 2797196 http://www.medworm.com/index.php?rid=2797195&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19747121%26dopt%3DAbstract Authors: Schieven GL The p38 kinase plays a central role in inflammation, and it has been the subject of extensive efforts in both basic research and drug discovery. This review summarizes the biology of the p38 kinase with a focus on its role in inflammation. The p38 kinase regulates the production of key inflammatory mediators by cells of the innate immune system, including TNFalpha, IL-1beta, and COX-2. In addition, p38 also acts downstream of cytokines such as TNFalpha, mediating some of their effects. Recently p38 has also been found to play a role in responses of T cells, including Th17 and regulatory T cells. Consistent with its important role in inflammation, recent evidence suggests cells may utilize a variety of feedback mechanisms to regulate and maintain p38 signal transduc... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2797195 Sat, 12 Sep 2009 23:00:00 +0100 2797195 http://www.medworm.com/index.php?rid=2797194&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19747122%26dopt%3DAbstract The objective of this review is to provide an update on the IN inhibitors reported in the last two years, including second generation strand transfer inhibitors (STI), recently developed hydroxylated aromatics, natural products, peptide, antibody and oligonucleotide inhibitors. Additionally, the targeting of IN cofactors such as LEDGF and Vpr will be discussed as novel strategies for the treatment of AIDS. PMID: 19747122 [PubMed - as supplied by publisher] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2797194 Sat, 12 Sep 2009 23:00:00 +0100 2797194 http://www.medworm.com/index.php?rid=2797193&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19747123%26dopt%3DAbstract Authors: Gianoulakis C There is significant experimental evidence implicating the endogenous opioid system (opioid peptides and opioid receptors) with the processes of reward and reinforcement. Indeed, many behaviors associated with reward and reinforcement, for example feeding behavior, are controlled by distinct components of the endogenous opioid system located in relevant brain regions. It has also been shown that regardless of their initial site of action many drugs of abuse, such as morphine, nicotine, cocaine, alcohol and amphetamines, induce an increase in the extracellular concentration of dopamine in the nucleus accumbens. This, increased secretion of dopamine in the nucleus accumbens seems to be a common effect of many drugs of abuse, and it was proposed that may mediate the... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2797193 Sat, 12 Sep 2009 23:00:00 +0100 2797193 http://www.medworm.com/index.php?rid=2720062&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19689360%26dopt%3DAbstract Authors: Lee J PMID: 19689360 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2720062 Fri, 21 Aug 2009 12:34:02 +0100 2720062 http://www.medworm.com/index.php?rid=2720061&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19689361%26dopt%3DAbstract Authors: Oh S, Kim KS, Chung YS, Shong M, Park SB In addition to its enormous impacts on an individual's quality of life, obesity is a daunting health problem in the world today and the increasing rate of obesity is now causing a severe burden on health care systems. Fortunately, the normalization or reduction of increased body fat reverses the obesity-associated morbidities, such as hypertension, glucose intolerance, dyslipidemia, and fatty liver diseases. However, the modification of lifestyle in a case of established clinical obesity is very difficult to achieve. Recent breakthroughs in relation to the molecular mechanism regulating body weight and energy metabolism give us hopes for the development of anti-obesity drugs. Even with the high social demand for an effective treatment f... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2720061 Fri, 21 Aug 2009 12:34:02 +0100 2720061 http://www.medworm.com/index.php?rid=2720060&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19689362%26dopt%3DAbstract Authors: Lee HK, Choi EB, Pak CS Since the discovery of rimonabant (Acomplia: 1), a large effort has been directed at the discovery of new, potent and selective CB(1)R antagonists that serve as anti obesity drugs. As a result, a number of compounds reached various stages of clinical trials by late 2008. However, the announcement by Sanofi-Aventis that they were discontinuing all ongoing trials with rimonabant, as a result of the finding that risks associated with depression and anxiety outweighed its benefits, had a major impact on this area. A wave of terminations of programs targeting the development of CB(1)R blockers for treatment of obesity ensued. However, abandoning this CB(1)R therapeutic target for anti-obesity drug development seems to be premature, since there are a number o... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2720060 Fri, 21 Aug 2009 12:34:02 +0100 2720060 http://www.medworm.com/index.php?rid=2720059&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19689363%26dopt%3DAbstract Authors: Jeon MK, Cheon HG Despite remarkable progress in the elucidation of energy balance and regulation, the development of new anti-obesity drugs is still at the stage of infancy. Herein we briefly reviewed several investigational anti-obesity agents currently under development, consisting of agents controlling appetite, modulating nutrient absorption and lipid metabolism, sensing and regulating nutrient status, stimulating energy expenditure, and reducing adiposity. In particular, two promising targets such as melanocortin-4 (MC-4) receptor and melanin concentrating hormone (MCH)-1 receptor will be highlighted in this review covering major medicinal chemistry efforts and biological aspects of the compounds synthesized. Considering the enthusiastic efforts to develop efficacious an... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2720059 Fri, 21 Aug 2009 12:34:02 +0100 2720059 http://www.medworm.com/index.php?rid=2720058&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19689364%26dopt%3DAbstract Authors: Min KH, Yoo J, Park HJ Many orphan G-protein-coupled receptors (GPCR) have emerged as potential obesity targets. The authors are interested in the computer-aided discovery and development of small molecule anti-obesity agents targeting GPCR. Computational modeling studies have mainly been conducted on ghrelin receptor (GHS-R), melanocortin 4-receptor (MC4R), melanin-concentrating hormone 1 receptor (MCH1R) and cannabinoid 1 receptor (CB1R) in recent publications. Here, a homology modeling strategy for these receptors will be introduced, and the key structural features of their active and inactive conformations will be reviewed. In addition, the authors describe the uses of virtual screening methods to identify novel antagonists of MCH1R and CB1R, which provide valuable example... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2720058 Fri, 21 Aug 2009 12:34:02 +0100 2720058 http://www.medworm.com/index.php?rid=2720057&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19689365%26dopt%3DAbstract Authors: Cai M, Nyberg J, Hruby VJ Current biological and pharmacological evidence suggests that the melanocortin 4 and melanocortin 3 receptors which are seven transmembrane G-protein coupled receptors (GPCRs) are involved in various aspects of energy balance and feeding behaviors in animals including humans. The natural endogenous ligands for these receptors are products of the gene pro-opiomelanocortin (POMC), and include alpha-melanocyte stimulating hormone, gamma-melanocyte stimulating hormone and perhaps other modified products of POMC. Thus well designed agonists and antagonists of these ligands might serve as drugs for the treatment of feeding disorders. However, these melanotropin peptides also can have other biological activities that involve the MC3R and MC4R, and these othe... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2720057 Fri, 21 Aug 2009 12:34:02 +0100 2720057 http://www.medworm.com/index.php?rid=2720056&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19689366%26dopt%3DAbstract Authors: Lee J, Song KS, Kang J, Lee SH, Lee J The prevalences of overweightedness and obesity are increasing globally at frightening rates, driven by social and economic changes. Furthermore, obesity is associated with the pathogeneses of major diseases, particularly diabetes and cardiovascular diseases. However, no satisfactorily safe, effective obesity drugs are commercially available at the present time. Only two drugs have been approved in the United States for the long-term treatment of obesity, sibutramine and orlistat. However, these drugs are minimally effective and have significant side effects, which are likely inhibit their use. Therefore, there is a huge opportunity to make a significant impact on the lives of obese people through the discovery and development of additiona... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2720056 Fri, 21 Aug 2009 12:34:02 +0100 2720056 http://www.medworm.com/index.php?rid=2720055&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19689367%26dopt%3DAbstract Authors: Player MR PMID: 19689367 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2720055 Fri, 21 Aug 2009 12:34:02 +0100 2720055 http://www.medworm.com/index.php?rid=2720054&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19689368%26dopt%3DAbstract Authors: Patel S, Player MR FMS is the exclusive receptor tyrosine kinase for colony-stimulating factor-1 (CSF-1, also known as M-CSF), which regulates the survival, proliferation, differentiation, and function of macrophage lineage cells. Since CSF-1 is over-expressed in many tumors and at sites of inflammation, small molecule inhibitors of CSF-1 appear to offer an attractive strategy for reducing macrophage numbers associated with cancer as well as autoimmune and inflammatory disease, such as rheumatoid arthritis (RA). Numerous FMS inhibitors with structurally distinct chemotypes have been developed and exhibit potent in vitro activity, but only a limited number of compounds have progressed clinically due to poor selectivity. To date, only a handful of FMS inhibitors have been tested... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2720054 Fri, 21 Aug 2009 12:34:02 +0100 2720054 http://www.medworm.com/index.php?rid=2720053&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19689369%26dopt%3DAbstract Authors: George D, Salmeron A Cot/Tpl-2/MAP3K8 is a serine/threonine protein kinase that is essential for lipopolysaccharide (LPS)-induced activation of the MEK/ERK pathway in macrophages as demonstrated in Cot/Tpl-2-deficient mice. Cot/Tpl-2 kinase activation plays an integral role in the production of pro-inflammatory cytokines such as TNF and IL-1beta in this immune cell type. Elevated levels of these cytokines have been clinically implicated as mediators of a number of autoimmune diseases, in particular, the pain and joint destruction of rheumatoid arthritis. By inference, pharmaceutical agents that inhibit Cot/Tpl-2 kinase have the potential to be novel and effective therapies for the treatment of these diseases. This review will describe the physiological regulation and importanc... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2720053 Fri, 21 Aug 2009 12:34:02 +0100 2720053 http://www.medworm.com/index.php?rid=2720052&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19689370%26dopt%3DAbstract Authors: Bamborough P, Callahan JF, Christopher JA, Kerns JK, Liddle J, Miller DD, Morse MA, Rumsey WL, Williamson R The IkappaB kinases (IKKs) are essential components of the signaling pathway by which the NF-kappaB p50/RelA transcription factor is activated in response to pro-inflammatory stimuli such as lipopolysaccharide (LPS) and tumor necrosis factor (TNFalpha). NF-kappaB signaling results in the expression of numerous genes involved in innate and adaptive immune responses. The pathway is also implicated in chronic inflammatory disorders including rheumatoid arthritis (RA), chronic obstructive pulmonary disorder (COPD), and asthma. Inhibition of the kinase activity of the IKKs is therefore a promising mechanism for intervention in these diseases. Here, we will review the literatu... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2720052 Fri, 21 Aug 2009 12:34:02 +0100 2720052 http://www.medworm.com/index.php?rid=2720051&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19689371%26dopt%3DAbstract Authors: Boschelli DH Members of the protein kinase C (PKC) family of serine/threonine kinases have been targeted for drug discovery for over 20 years, initially focusing on inhibitors of the classic PKCs, which include the alpha, beta and gamma isoforms. Recently, inhibition of the activity of the novel PKC isoforms, namely Theta, delta, epsilon and eta has become a focus of research. PKCTheta, first identified in 1992, is a key enzyme in the regulation of T cell activation and survival. While T cells play critical roles in initiating and controlling the immune response, inappropriate or extended stimulation of T cells is responsible for many chronic inflammatory diseases. Mice with an engineered deficiency in PKCTheta have reduced incidence and severity of several inflammatory disord... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2720051 Fri, 21 Aug 2009 12:34:02 +0100 2720051 http://www.medworm.com/index.php?rid=2720050&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19689372%26dopt%3DAbstract Authors: Karcher SC, Laufer SA Inflammation is a complex immune response to cellular and tissue damage caused by physical, chemical, immunological, or microbial stimuli [1]. Prior to the successful launch of the anti-cytokine biologics [2-4], therapeutic approaches for the treatment of chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease were associated with severe side effects. Although biological agents have revolutionized the treatment of inflammatory disorders, the high costs and inconvenient dosing regimens would greatly benefit from novel safe and effective orally active inhibitors of tumor necrosis factor (TNF) alpha and interleukin (IL) 1beta. The clinical benefit of anti-cytokine therapy [5] and the central role of the p38 mitogen-activated... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2720050 Fri, 21 Aug 2009 12:34:02 +0100 2720050 http://www.medworm.com/index.php?rid=2720049&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19689373%26dopt%3DAbstract Authors: Player MR PMID: 19689373 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2720049 Fri, 21 Aug 2009 12:34:02 +0100 2720049 http://www.medworm.com/index.php?rid=2720048&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19689374%26dopt%3DAbstract Authors: Burkhard K, Smith S, Deshmukh R, MacKerell AD, Shapiro P Activation of the extracellular signal-regulated kinase (ERK) signaling pathway has been implicated in mediating a diverse array of cellular functions including cell differentiation, proliferation, and inflammatory responses. In this review, we will discuss approaches to identify inhibitors of ERK proteins through targeting ATP-dependent and ATP-independent mechanisms. Given the diversity of ERK substrates and the importance of ERK signaling in normal cell functions, emphasis will be placed on the methods for identifying small molecular weight compounds that are substrate selective through ATP-independent interactions and potentially relevant to inflammatory processes. The approach for selective targeting of ERK substrat... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2720048 Fri, 21 Aug 2009 12:34:02 +0100 2720048 http://www.medworm.com/index.php?rid=2720047&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19689375%26dopt%3DAbstract Authors: Sahu N, August A Interleukin-2-inducible T cell kinase (ITK) is a non-receptor tyrosine kinase expressed in T cells, NKT cells and mast cells which plays a crucial role in regulating the T cell receptor (TCR), CD28, CD2, chemokine receptor CXCR4, and FcepsilonR-mediated signaling pathways. In T cells, ITK is an important mediator for actin reorganization, activation of PLCgamma, mobilization of calcium, and activation of the NFAT transcription factor. ITK plays an important role in the secretion of IL-2, but more critically, also has a pivotal role in the secretion of Th2 cytokines, IL-4, IL-5 and IL-13. As such, ITK has been shown to regulate the development of effective Th2 response during allergic asthma as well as infections of parasitic worms. This ability of ITK to regul... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2720047 Fri, 21 Aug 2009 12:34:02 +0100 2720047 http://www.medworm.com/index.php?rid=2720046&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19689376%26dopt%3DAbstract Authors: LoGrasso PV, Feng Y Inhibitors of Rho kinase (ROCK) have many potential therapeutic applications. The biological focus of this overview will be on the role of ROCK in inflammatory disorders such as multiple sclerosis and asthma. Many ROCK inhibitors have been described in the primary and patent literature, and a diverse range of chemical scaffolds is beginning to emerge. Some of the structural classes that will be highlighted in this review include: isoquinolines, indazoles, amino-furazans, dihydropyrimidines, aminopyrimidines, benzodioxane carboxamides, benzimidazoles, and chroman amides. PMID: 19689376 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2720046 Fri, 21 Aug 2009 12:34:02 +0100 2720046 http://www.medworm.com/index.php?rid=2720045&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19689377%26dopt%3DAbstract Authors: Wang Z, Wesche H, Stevens T, Walker N, Yeh WC Interleukin-1 receptor-associated kinases (IRAKs) are key components in the signal transduction pathways utilized by interleukin-1 receptor (IL-1R), interleukin-18 receptor (IL-18R), and Toll-like receptors (TLRs). Out of four members in the mammalian IRAK family, IRAK-4 is considered to be the "master IRAK", the only family member indispensable for IL-1R/TLR signaling. In humans, mutations resulting in IRAK-4 deficiency have been linked to susceptibility to bacterial infections, especially recurrent pyogenic bacterial infections. Furthermore, knock-in experiments by several groups have clearly demonstrated that IRAK-4 requires its kinase activity for its function. Given the critical role of IRAK-4 in inflammatory processes, modula... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2720045 Fri, 21 Aug 2009 12:34:02 +0100 2720045 http://www.medworm.com/index.php?rid=2720044&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19689378%26dopt%3DAbstract Authors: Ameriks MK, Venable JD In recent years, pharmaceutical companies have increasingly focused on phosphoinositide 3-kinases delta (PI3Kdelta) and gamma (PI3Kgamma) as therapeutic targets for the treatment of inflammatory and autoimmune diseases. All class 1 PI3-kinases (alpha/beta/gamma/delta) generate phospholipid second messengers that help govern cellular processes such as migration, proliferation, and apoptosis. PI3K delta/ gamma lipid kinases are mainly restricted to the hematopoetic system whereas PI3K alpha/beta are ubiquitously expressed, thus raising potential toxicity concerns for chronic indications such as asthma and rheumatoid arthritis. Therefore, the challenge in developing a small molecule inhibitor of PI3K is to define and attain the appropriate isoform selectivi... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2720044 Fri, 21 Aug 2009 12:34:02 +0100 2720044 http://www.medworm.com/index.php?rid=2545274&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19442202%26dopt%3DAbstract Authors: Li M PMID: 19442202 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2545274 Sun, 28 Jun 2009 03:03:03 +0100 2545274 http://www.medworm.com/index.php?rid=2545272&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19442203%26dopt%3DAbstract Authors: Shen Z, Yang Q, You Q As trans-membrane proteins located in cytoplasm and organelle membrane, potassium (K(+)) channels are generally divided into four super-families: voltage-gated K(+) channels (K(v)), Ca(2+)-activated K(+) channels (K(Ca)), inwardly rectifying K(+) channels (K(ir)) and two-pore domain K(+) channels (K(2P)). Since dysfunctions of K(+) channels would induce many diseases, various studies toward their functions in physiologic and pathologic process have been extensively launched. This review focuses on the recent advances of K(+) channels in tumor progression, including the brief introduction of K(+) channels, the role of K(+) channels in tumor cells, the possible mechanism of action at cellular level, and the possible application of K(+) channel modulators in... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2545272 Sun, 28 Jun 2009 03:03:03 +0100 2545272 http://www.medworm.com/index.php?rid=2545270&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19442204%26dopt%3DAbstract Authors: Du L, Li M, You Q The human ether-a-go-go related gene (hERG) potassium channel is critical to the QT interval in the human heart measured by the electrocardiogram (ECG). The blockade of hERG would induce undesired lethal arrhythmia, named torsades de pointes (TdP), a rare but life-threatening symptom. Although a large number of experimental studies on hERG have been conducted so far, knowledge of how known ligands bind to hERG still remains sketchy and has been a major hindrance in the effort to designing novel medicinal molecules devoid of hERG activity in the hope of improving drug safety. This review summarizes several studies on ligand-hERG interactions by in silico receptor-based and ligand-based modeling approaches during recent years. These efforts could aid tremendous... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2545270 Sun, 28 Jun 2009 03:03:03 +0100 2545270 http://www.medworm.com/index.php?rid=2545268&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19442205%26dopt%3DAbstract Authors: Yang Q, Wang X, Du L, Li M, You Q Attributed to the extensive researches towards the functions of Kv1.5 gene (also known as KCN5A gene), the therapeutic significances of Kv1.5 channel have been paid special attentions to cardiovascular diseases as well as tumor, the top two public-health problems for the aging population. During recent years, the hindrance for developing cardiovascular drugs is how to discriminate their therapeutic effect from cardiotoxicities. Therefore, targeting Kv1.5 gene, which encodes the atrial selective I(Kur) potassium channel, has been confirmed as an appealing strategy for the treatment of atrial diseases. Moreover, the functions of Kv1.5 gene in carcinoma progression have also provoked a flurry of research in the hope of developing adjunctive or co... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2545268 Sun, 28 Jun 2009 03:03:03 +0100 2545268 http://www.medworm.com/index.php?rid=2545266&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19442206%26dopt%3DAbstract Authors: Ye D, Wang J, Yu K, Zhou Y, Jiang H, Chen K, Liu H Potassium ion (K(+)) channels consist of a ubiquitous family of membrane proteins that play critical roles in a wide variety of physiological processes, such as the regulation of neuronal excitability, muscle contraction, cell proliferation, and insulin secretion. Due to their pivotal functions in biological systems, K(+) channels have long been attractive targets for the rational drug design on the basis of their structures and interaction mechanisms. Various small-molecular compounds and toxins have been discovered to act as K(+) channel modulators. In the present review, we will first briefly discuss current knowledge of the structures and functions of K(+) channels, and then review the recent strategies for the discovery o... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2545266 Sun, 28 Jun 2009 03:03:03 +0100 2545266 http://www.medworm.com/index.php?rid=2545264&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19442207%26dopt%3DAbstract Authors: Matulenko MA, Scanio MJ, Kort ME The voltage-gated sodium channels are a family of proteins that control the flow of sodium ions across cell membranes. Considerable data support the hypothesis that hyperexcitability and spontaneous action potential firing in peripheral sensory neurons mediated by voltage-gated sodium channels contribute to the pathophysiology of chronic pain. Sodium channel blockers are, therefore, appealing entities for therapeutic intervention in painful human neuropathies. This review will focus on the latest advances in the development of small molecule sodium channel blockers and their application to the treatment of chronic pain. PMID: 19442207 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2545264 Sun, 28 Jun 2009 03:03:03 +0100 2545264 http://www.medworm.com/index.php?rid=2545262&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19442208%26dopt%3DAbstract Authors: Yamamoto T, Takahara A The voltage-dependent N-type calcium channel (Ca(v)2.2), which is distributed in the nerve endings of the central and peripheral nerves, is known to be strongly associated with the pathological processes of cerebral ischemia and neuropathic pain. Ziconotide, the chemically synthesized version of the 25-residue peptide marine toxin omega-conotoxin MVIIA, has been approved as an analgesic drug for severe chronic pain treatment. A blockade of N-type calcium channels has been suggested for reducing the neuronal injury occurring from ischemia/reperfusion events. Therefore, many efforts have been made to develop systemically available small-molecule N-type calcium channel blockers thus far. This review focuses on the latest updates concerning small-molecule N-... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2545262 Sun, 28 Jun 2009 03:03:03 +0100 2545262 http://www.medworm.com/index.php?rid=2545260&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19442209%26dopt%3DAbstract Authors: Zuliani V, Patel MK, Fantini M, Rivara M The voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability. Abnormal activity of sodium channels is related to several pathological processes, including cardiac arrhythmias, epilepsy, chronic pain, neurodegenerative diseases and spasticity. In view of this, VGSCs are considered important therapeutic targets for the treatment of these disorders. To date, nine VGSC isoforms have been identified and have a distinct pattern of expression within the human body. In addition, VGSCs also have distinct electrophysiological profiles with differing activation and inactivation states. As such, there is a concerted effort to develop not only isoform selective antagonists, but also antagonists that exhibit ... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2545260 Sun, 28 Jun 2009 03:03:03 +0100 2545260 http://www.medworm.com/index.php?rid=2545258&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19519457%26dopt%3DAbstract Authors: Lee D PMID: 19519457 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2545258 Sun, 28 Jun 2009 03:03:03 +0100 2545258 http://www.medworm.com/index.php?rid=2545256&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19519458%26dopt%3DAbstract Authors: Hunt JA, Lu Z Epidemiological studies have demonstrated an inverse correlation between plasma concentrations of high-density lipoprotein cholesterol (HDL-C) and incidence of coronary heart disease (CHD); thus new therapies for raising HDL-C levels have been the focus of significant efforts by the cardiovascular medicine community. Inhibition of cholesteryl ester transfer protein (CETP) is one approach to increasing HDL-C concentrations. CETP is a plasma glycoprotein that mediates the transfer of cholesteryl esters from HDL to the apoB-containing lipoproteins, with a balanced transfer of triglycerides. Inhibition of CETP results in an accumulation of cholesteryl esters in HDL, thus resulting in increased HDL-C. Pharmacological inhibition of CETP in humans has been shown to resu... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2545256 Sun, 28 Jun 2009 03:03:03 +0100 2545256 http://www.medworm.com/index.php?rid=2545254&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19519459%26dopt%3DAbstract Authors: Martres P The discovery of HM74a as a high affinity receptor for nicotinic acid has opened up new areas for investigation. Since its discovery, several new chemical entities have been reported as HM74a agonists. One of them, MK-0354, has been tested in phase II studies, but despite significant decreases in Free Fatty Acid levels with absence of flushing events in clinical studies, it failed to demonstrate effects on LDL-Cholesterol, Triglycerides and HDL-Cholesterol. These surprising results lead to questions about the reality of HM74a as the unique receptor responsible for the lipid modulating effects of nicotinic acid. This review summarizes these recent developments, and the novel HM74a antagonist structures recently published. PMID: 19519459 [PubMed - in process] (Sour... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2545254 Sun, 28 Jun 2009 03:03:03 +0100 2545254 http://www.medworm.com/index.php?rid=2545252&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19519460%26dopt%3DAbstract This article reviews the development of Kv1.5 blockers. The discovery and clinical progress of the non-selective Kv1.5 blockers vernakalant and AVE-0118 are highlighted. More selective Kv1.5 blockers in pre-clinical stages of discovery are then reviewed, with a focus on compounds that have been investigated for their in vivo effects on atrial repolarization or on efficacy in pre-clinical models of atrial fibrillation. PMID: 19519460 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2545252 Sun, 28 Jun 2009 03:03:03 +0100 2545252 http://www.medworm.com/index.php?rid=2545250&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19519461%26dopt%3DAbstract Authors: Marino JP Soluble epoxide hydrolase (sEH) is a cross-functional target, with the potential for therapeutic utility in the areas of hypertension, inflammation, and organ-protection. Promising target validation has emerged around soluble epoxide hydrolase in recent years which suggests that small molecule inhibitors may have utility in cardio protection, glucose regulation, hypertension, inflammation, and organ protection. Based on the diversity of chemical classes of sEH inhibitors reported in the literature, there exists a real opportunity to definitively determine the best therapeutic utility for an sEH inhibitor. Recent advances in target validation and tool compounds from medicinal chemistry efforts will be described. PMID: 19519461 [PubMed - in process] (Source: Curren... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2545250 Sun, 28 Jun 2009 03:03:03 +0100 2545250 http://www.medworm.com/index.php?rid=2323351&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19355986%26dopt%3DAbstract Authors: Wiest O PMID: 19355986 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2323351 Sat, 11 Apr 2009 13:16:46 +0100 2323351 http://www.medworm.com/index.php?rid=2323349&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19355987%26dopt%3DAbstract Authors: Hauser AT, Jung M, Jung M Epigenetics is defined as heritable changes in gene expresssion, i.e. the presentation of a certain phenotype, without alterations to the genetic code. This is a central phenomenon in developmental biology but also for the pathogenesis of a variety of diseases, e.g. for cancer in the case of silencing of tumor suppressor proteins. Reversible histone acetylation is an important player within the epigenetic machinery and histone deacetylases are the best studied epigenetic target for drug discovery. A first drug (vorinostat) is already approved for human cancer treatment. The strategies and protocols for monitoring histone deacetylase (HDAC) activity are an integral part of drug discovery approaches towards new HDAC inhibitors and will be reviewed in th... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2323349 Sat, 11 Apr 2009 13:16:46 +0100 2323349 http://www.medworm.com/index.php?rid=2323347&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19355988%26dopt%3DAbstract Authors: Ficner R The deacetylation of modified lysine residues of histones and other proteins is catalyzed by histone deacetlyases (HDACs). HDACs play an important role in the regulation of many biological processes such as cell-cycle, cell differentiation and survival. Since the inhibition of HDACs leads to growth arrest, differentiation or apoptosis of tumor cell lines, HDACs are promising targets for cancer therapy. Knowledge of the three-dimensional structures of HDACs with bound substrate or inhibitor molecules is a prerequisite for rational structure-based drug design. Here recent developments in the crystal structure analysis of human HDAC4, HDAC7, and HDAC8, which all belong to the family of zinc ion-dependent HDACs, are described. Crystallographic and biochemical studies of t... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2323347 Sat, 11 Apr 2009 13:16:46 +0100 2323347 http://www.medworm.com/index.php?rid=2323345&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19355989%26dopt%3DAbstract Authors: Wang D The catalytic activity of the histone deacetylase (HDAC) enzymes is directly relevant to the pathogenesis of cancer as well as several other diseases. HDAC inhibitors have been shown to have the potential to treat several types of cancers. The role of computational study of the HDAC enzymes is reviewed, with particular emphasis on the important role of molecular modeling to the development of HDAC inhibitors with improved efficacy and selectivity. The use of two computational approaches-one structure-based, and the second ligand-based-toward inhibitors against the different HDAC sub-classes, are summarized. PMID: 19355989 [PubMed - in process] (Source: Current Topics in Medicinal Chemistry) Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2323345 Sat, 11 Apr 2009 13:16:46 +0100 2323345 http://www.medworm.com/index.php?rid=2323343&cid=s_37256_59_f&fid=37256&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19355990%26dopt%3DAbstract Authors: Wiech NL, Fisher JF, Helquist P, Wiest O The dynamics of gene expression are regulated by histone acetylases (HATs) and histone deacetylases (HDACs) that control the acetylation state of lysine side chains of the histone proteins of chromatin. The catalytic activity of these two enzymes remodels chromatin to control gene expression without altering gene sequence. Treatment of cancer has been the primary target for the clinical development of HDAC inhibitors, culminating in approval for the first HDAC inhibitor for the treatment of cutaneous T cell lymphoma. Beyond cancer, HDAC inhibition has potential for the treatment of many other diseases. The HDAC inhibitors phenylbutyric acid, valproic acid, and suberoylanilide hydroxamic acid (SAHA) have been shown to correct errant gene... Current Topics in Medicinal Chemistry journals http://www.medworm.com/rss/comments.php?id=2323343 Sat, 11 Apr 2009 13:16:46 +0100 2323343