Jadhav Prabhakar K, Schiffler Matthew A, Gavardinas Kostas, Kim Euibong J, Matthews Donald P, Staszak Michael A, Coffey D Scott, Shaw Bruce W, Cassidy Kenneth C, Brier Richard A, Zhang Yuke, Christie Robert M, Matter William F, Qing Keyun, Durbin Jim D, Wang Yong, Deng Gary G
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.
ACS Med Chem Lett. 2014 Aug 27;5(10):1138-42. doi: 10.1021/ml500283g. eCollection 2014 Oct 9.
Cathepsin S (Cat S) plays an important role in many pathological conditions, including abdominal aortic aneurysm (AAA). Inhibition of Cat S may provide a new treatment for AAA. To date, several classes of Cat S inhibitors have been reported, many of which form covalent interactions with the active site Cys25. Herein, we report the discovery of a novel series of noncovalent inhibitors of Cat S through a medium-throughput focused cassette screen and the optimization of the resulting hits. Structure-based optimization efforts led to Cat S inhibitors such as 5 and 9 with greatly improved potency and drug disposition properties. This series of compounds binds to the S2 and S3 subsites without interacting with the active site Cys25. On the basis of in vitro potency, selectivity, and efficacy in a CaCl2-induced AAA in vivo model, 5 (LY3000328) was selected for clinical development.
组织蛋白酶S（Cat S）在包括腹主动脉瘤（AAA）在内的许多病理状况中发挥着重要作用。抑制Cat S可能为AAA提供一种新的治疗方法。迄今为止，已报道了几类Cat S抑制剂，其中许多与活性位点Cys25形成共价相互作用。在此，我们报告通过中通量聚焦盒式筛选以及对所得命中化合物的优化，发现了一系列新型的Cat S非共价抑制剂。基于结构的优化工作产生了诸如5和9之类的Cat S抑制剂，其效力和药物处置特性得到了极大改善。这一系列化合物与S2和S3亚位点结合，而不与活性位点Cys25相互作用。基于体外效力、选择性以及在氯化钙诱导的体内AAA模型中的疗效，选择了5（LY3000328）进行临床开发。
