Progress in medicinal chemistry最新文献_第8页

Progress in the development of small molecule therapeutics targeting Th17 cell function for the treatment of immune-inflammatory diseases. 靶向Th17细胞功能治疗免疫炎性疾病的小分子药物研究进展

Progress in medicinal chemistry Pub Date : 2011-01-01 DOI: 10.1016/B978-0-12-381290-2.00003-3

Stephen Shuttleworth, Paul Townsend, Franck Silva, Alexander Cecil, Thomas Hill, Cyrille Tomassi, Helen Rogers, Rebecca Harrison

引用次数: 8

The Journey to the Discovery of Boceprevir: an NS3-NS4 HCV protease inhibitor for the treatment of chronic hepatitis C. Boceprevir的发现之旅:用于治疗慢性丙型肝炎的NS3-NS4 HCV蛋白酶抑制剂。

Progress in medicinal chemistry Pub Date : 2010-01-01 DOI: 10.1016/S0079-6468(10)49001-3

Kevin X Chen, F George Njoroge

引用次数: 27

A decade of progress in the discovery and development of 'atypical' antipsychotics. 发现和开发“非典型”抗精神病药物的十年进展。

Progress in medicinal chemistry Pub Date : 2010-01-01 DOI: 10.1016/S0079-6468(10)49002-5

Gregor J MacDonald, José Manuel Bartolomé

引用次数: 20

Computational analysis of structure-activity relationships. 构效关系的计算分析。

Progress in medicinal chemistry Pub Date : 2010-01-01 DOI: 10.1016/S0079-6468(10)49004-9

Peter Gedeck, Christian Kramer, Peter Ertl

引用次数: 22

Structural trends among second-generation voltage-gated sodium channel blockers. 第二代电压门控钠通道阻滞剂的结构趋势。

Progress in medicinal chemistry Pub Date : 2010-01-01 DOI: 10.1016/S0079-6468(10)49003-7

Mark I Kemp

引用次数: 15

Medicinial chemistry. Preface. Medicinial化学。前言。

Progress in medicinal chemistry Pub Date : 2010-01-01 DOI: 10.1016/S0079-6468(10)49007-4

G Lawton, D R Witty

引用次数: 0

H+/K+ ATPase inhibitors in the treatment of acid-related disorders. H+/K+ atp酶抑制剂治疗酸相关疾病。

Progress in medicinal chemistry Pub Date : 2009-01-01 DOI: 10.1016/S0079-6468(08)00203-8

Mark Bamford

引用次数: 18

Medicinal chemistry by the numbers: the physicochemistry, thermodynamics and kinetics of modern drug design. 数字药物化学:现代药物设计的物理化学、热力学和动力学。

Progress in medicinal chemistry Pub Date : 2009-01-01 DOI: 10.1016/s0079-6468(09)04801-2

Graham F Smith

引用次数: 33

Progress in the development of beta-secretase inhibitors for Alzheimer's disease. 阿尔茨海默病β -分泌酶抑制剂的研究进展。

Progress in medicinal chemistry Pub Date : 2009-01-01 DOI: 10.1016/s0079-6468(09)04804-8

Jeffrey S Albert

{"title":"Progress in the development of beta-secretase inhibitors for Alzheimer's disease.","authors":"Jeffrey S Albert","doi":"10.1016/s0079-6468(09)04804-8","DOIUrl":"https://doi.org/10.1016/s0079-6468(09)04804-8","url":null,"abstract":"<p><p>Since the original identification of BACE in 1999 and until quite recently, BACE was often regarded as a \"difficult\" drug target, much as renin has proven to be. The reasons for this include the following. First, the long and shallow nature of the substrate binding pocket suggested that it would not be possible to identify small molecule drugs that could have adequate binding affinity. Second, functional groups that typically interact with the active site aspartates are usually highly polarized and, therefore, contribute to reduced CNS localization. Early BACE inhibitors were all designed using knowledge of the peptide substrates and usually contained some variation of a few well-known transition-state isosteres. While these had great impact on fundamental understanding of the enzyme structure and key interaction regions, they were very large, very polar, and had essentially no CNS availability. Continued progress by reducing the peptidic nature of these compounds resulted in incremental advances and has provided compounds that meet, or nearly meet, typical CNS drug-like criteria. The challenges associated with peptidic starting points inspired innovative new approaches to search for different starting points. Several groups employed high concentration screening (ligand concentration 100 microM and higher) to find weak hits after conventional screening (typically at 10 microM) failed to find more potent ones. Fragment-based methods have also been developed to identify even weaker hits (IC50 1 mM and greater). This was accomplished through the evolution and refinement of several detection methodologies including calorimetry, surface plasmon resonance, NMR, and crystallography. Coupled with detailed structural understanding of ligand-enzyme interactions and focus on maintaining ligand efficiency, these developments have resulted in several examples where potency was improved by 10,000-fold to afford compounds with IC50 values < 10 nM and promising drug-like characteristics. Together, all these efforts have afforded a diverse array of chemotypes as BACE inhibitors. Early work focused on improving BACE potency in isolated enzyme assays. However, most of these compounds showed potency reductions in cellular assays. Continued improvements in drug properties and in understanding of the physiologically relevant conditions have resulted in many compounds that show strong potency in both isolated and cellular assays. Several compounds have shown reduction of Abeta using rodent in-vivo models both peripherally and in the brain. Recently, one compound has demonstrated reduction of brain Abeta levels in a non-human primate. Phase I clinical trials were initiated on BACE inhibitor CTS-21166 from CoMentis in July of 2007. This compound derives from the earliest described peptidic inhibitors such as OM99-2 [58] but no details have been reported. In addition to strategies involving small molecule inhibitors of BACE and gamma-secretase to reduce Abeta levels","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/s0079-6468(09)04804-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30163920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 35

Progress in medicinal chemistry. Preface. 药物化学进展。前言。

Progress in medicinal chemistry Pub Date : 2009-01-01 DOI: 10.1016/S0079-6468(08)00208-7

G Lawton, D R Witty

引用次数: 1