进步发展的β分泌酶抑制剂对阿尔茨海默氏症。

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艾伯特JS

进步发展的β分泌酶抑制剂对阿尔茨海默氏症。

地中海食物化学2009;48:133 - 61。

PubMed ID

21544959 (在PubMed

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文摘

自1999年最初的识别确定新基点,直到最近,确定新基点通常被视为一个“困难”药物目标,肾素已被证明是。原因包括以下。首先,长和浅底物性质绑定口袋表明它不可能确定小分子药物,可以有足够的亲和力。第二,天冬氨酸盐官能团,通常与活性位点通常是高度分化,因此,有助于减少中枢神经系统本地化。早期确定新基点抑制剂都使用的知识设计肽底物,通常包含一些变异的几个著名的过渡态等排物。虽然这些基本的认识有很大影响酶的结构和关键互动区域,它们非常大,非常极地,基本上没有中枢神经系统的可用性。持续进步通过减少peptidic这些化合物的性质导致增量进步和满足提供了化合物,或几乎见面,典型的中枢神经系统药物类标准。挑战与peptidic起点启发创新的新方法来寻找不同的起点。几组采用高浓度筛查(配体浓度100 microM和更高版本)找到弱冲击后常规筛查(通常10 microM)没有找到更有效的。Fragment-based方法也被开发来识别甚至弱(IC50 1毫米和更大)。 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, the application of biological agents has been under investigation since the identification of Abeta. The earliest efforts in this area failed. Despite encouraging results in preclinical models, immunization against Abeta by administration of AN-1792 from Elan led to development of aseptic meningoencephalitis in 6% of the patients receiving the drug. Nevertheless, continued efforts with other biological approaches appear encouraging. Most advanced in clinical trials is bapineuzumab from Elan, which is in Phase III clinical trials. This is a humanized monoclonal antibody against Abeta plaques. A recent monograph is devoted to progress in these areas. Taken together, considerable progress has been made in developing CNS-penetrant agents that reduce AP levels and in providing validation that such agents will be therapeutically beneficial for the treatment of Alzheimer's disease.

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药物靶点

药物	目标	类	生物	药理作用	行动
cts - 21166	β分泌酶1	蛋白质	人类	是的	抑制剂	细节