Progress in medicinal chemistry最新文献

英文中文

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

Q1 Pharmacology, Toxicology and Pharmaceutics

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。

Q1 Pharmacology, Toxicology and Pharmaceutics

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。

Q1 Pharmacology, Toxicology and Pharmaceutics

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。

Q1 Pharmacology, Toxicology and Pharmaceutics

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。

Q1 Pharmacology, Toxicology and Pharmaceutics

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

Q1 Pharmacology, Toxicology and Pharmaceutics

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

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。

Q1 Pharmacology, Toxicology and Pharmaceutics

Progress in medicinal chemistry

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

Jeffrey S Albert

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

自1999年首次发现BACE以来，直到最近，BACE通常被认为是一个“困难”的药物靶点，就像肾素一样。其原因包括以下几点。首先，底物结合袋的长而浅的性质表明，不可能识别出具有足够结合亲和力的小分子药物。其次，通常与活性位点天冬氨酸相互作用的官能团通常是高度极化的，因此有助于减少中枢神经系统的定位。早期的BACE抑制剂都是根据肽底物的知识设计的，通常含有一些已知的过渡态同分异构体的变异。虽然这些对酶结构和关键相互作用区域的基本理解有很大影响，但它们非常大，非常极性，基本上没有中枢神经系统可用性。通过减少这些化合物的肽类性质的持续进展导致了渐进式的进展，并提供了符合或几乎符合典型中枢神经系统药物样标准的化合物。与肽起点相关的挑战激发了寻找不同起点的创新方法。几个小组采用高浓度筛选(配体浓度为100微米及以上)发现弱命中，而常规筛选(通常为10微米)未能找到更有效的命中。基于碎片的方法也被开发出来以识别更弱的撞击(IC50为1毫米或更大)。这是通过发展和改进几种检测方法来完成的，包括量热法、表面等离子体共振、核磁共振和晶体学。再加上对配体-酶相互作用的详细结构理解和对保持配体效率的关注，这些发展已经产生了几个例子，其中效价提高了10,000倍，从而提供IC50值< 10 nM的化合物和有希望的药物样特性。总之，所有这些努力提供了多种化学型作为BACE抑制剂。早期的工作集中在提高BACE在分离酶检测中的效力。然而，大多数这些化合物在细胞分析中显示效力降低。药物性质的不断改进和对生理相关条件的理解，导致许多化合物在分离和细胞分析中都显示出强大的效力。几种化合物在啮齿类动物体内模型中显示出外周和大脑中β的减少。最近，一种化合物被证明可以降低非人类灵长类动物大脑中的β水平。2007年7月，CoMentis公司启动了BACE抑制剂CTS-21166的I期临床试验。该化合物来源于最早被描述的肽抑制剂，如OM99-2[58]，但没有详细报道。除了使用BACE和γ -分泌酶的小分子抑制剂来降低β水平的策略外，自发现β以来，生物制剂的应用一直在研究中。在这个领域最早的努力失败了。尽管在临床前模型中取得了令人鼓舞的结果，但通过给药Elan公司的AN-1792对Abeta进行免疫接种，导致6%接受该药的患者发生无菌性脑膜脑炎。然而，其他生物学方法的持续努力似乎令人鼓舞。临床试验中最先进的是Elan公司的bapineuzumab，目前正在进行III期临床试验。这是一种人源化的抗β斑块单克隆抗体。最近有一本专著专门讨论这些领域的进展。综上所述，在开发可降低AP水平的cns渗透剂以及验证此类药物对阿尔茨海默病的治疗有益方面取得了相当大的进展。

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引用次数: 35

Advances in the design of 5-HT6 receptor ligands with therapeutic potential. 具有治疗潜力的5-HT6受体配体的设计进展。

Q1 Pharmacology, Toxicology and Pharmaceutics

Progress in medicinal chemistry

Pub Date : 2009-01-01 DOI: 10.1016/s0079-6468(09)04805-x

David Witty, Mahmood Ahmed, Tsu Tshen Chuang

引用次数: 22

The adenosine A1 receptor and its ligands. 腺苷A1受体及其配体。

Q1 Pharmacology, Toxicology and Pharmaceutics

Progress in medicinal chemistry

Pub Date : 2009-01-01 DOI: 10.1016/S0079-6468(08)00204-X

Peter G Nell, Barbara Albrecht-Küpper

引用次数: 24

Beginning of the 'numbers' era of medicinal chemistry. Preface. 药物化学的“数字”时代开始了。前言。

Q1 Pharmacology, Toxicology and Pharmaceutics

Progress in medicinal chemistry

Pub Date : 2009-01-01 DOI: 10.1016/S0079-6468(09)04810-3

G Lawton, D R Witty

引用次数: 0

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