Gamma Secretase Modulators: New Alzheimer's Drugs on the Horizon?
Gamma Secretase Modulators: New Alzheimer's Drugs on the Horizon?
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DOI：
10.1021/acs.jmedchem.5b01960
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发表时间：
2016-08-25
影响因子：
7.3
通讯作者：
Blain, Jean-Francois
中科院分区：
文献类型：
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作者：
Bursavich, Matthew G.;Harrison, Bryce A.;Blain, Jean-Francois
快速老龄化的人口迫切需要阿尔茨海默病的新疗法。尽管进行了多年的药物研究，但临床成功有限，近年来有几种疾病修饰疗法失败。在令人信服的遗传证据的基础上，制药业已经非常重视脑β淀粉样蛋白（A β），通过抗体或靶向负责其生产的蛋白酶将其去除。在这个角度来看，我们专注于开发的小分子，提高活性的一个这样的蛋白酶，γ分泌酶，通过变构结合位点，优先增加浓度较短的不，淀粉样蛋白A β物种。在由于较差的药物样性质而导致的一些早期失败之后，该行业现在正处于将γ分泌酶调节剂用于临床机制验证研究的尖端，该研究将联合收割机的效力和功效与改善的药物样性质结合起来，例如。低cLogP、高中枢神经系统多参数优化评分和高spa特征。
The rapidly aging population desperately requires new therapies for Alzheimer's disease. Despite years of pharmaceutical research, limited clinical success has been realized, with several failed disease modification therapies in recent years. On the basis of compelling genetic evidence, the pharmaceutical industry has put a large emphasis on brain-beta amyloid (A beta) either through its removal via antibodies or by targeting the proteases responsible for its production. In this Perspective, we focus on the development of small molecules that improve the activity of one such protease, gamma secretase, through an allosteric binding site to preferentially increase the concentration of the shorter not,amyloidogenic A beta species. After a few early failures due to poor drug-like properties, the industry is now on the cusp of delivering gamma secretase modulators for clinical proof-of-mechanism studies that combine potency and efficacy with improved drug-like properties such as. lower cLogP, high central nervous system multiparameter optimization scores, and high spa character.