asunaprevir（BMS-650032）的发现，一种口服有效的 NS3 蛋白酶抑制剂，用于治疗丙型肝炎病毒感染。
The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection.
机构信息
Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut, 06492, United States.
出版信息
J Med Chem. 2014 Mar 13;57(5):1730-52. doi: 10.1021/jm500297k. Epub 2014 Mar 5.
The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).
本文介绍了asunaprevir（BMS-650032，24）的发现。这种三肽酰基磺酰胺 NS3/4A 酶抑制剂目前正处于治疗丙型肝炎病毒感染的 III 期临床试验阶段。24 的发现得益于采用离体兔心模型筛选出引起心血管（CV）副作用（HR 和 SNRT 改变）的化合物，这导致该化学系列的早期先导化合物 BMS-605339（1）退出临床试验。与 CV 作用相关的构效关系（SARs）表明，分子 P2*亚基的微小结构变化对给定化合物的 CV 特征有重大影响。抗病毒活性、临床前 PK 特征和大鼠及犬的毒理学研究支持 BMS-650032（24）的临床开发。
Zotero 插件