向着博赛泼维的第二代：作为 HCV NS3 蛋白酶抑制剂中 2,2-二甲基环丙基脯氨酸的 P2 取代基的替代物，二硫戊环。
Towards the second generation of Boceprevir: Dithianes as an alternative P2 substituent for 2,2-dimethyl cycloproyl proline in HCV NS3 protease inhibitors.
机构信息
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
出版信息
Bioorg Med Chem Lett. 2010 Mar 1;20(5):1689-92. doi: 10.1016/j.bmcl.2010.01.037. Epub 2010 Jan 20.
Hepatitis C (HCV) infection is a global health crisis leading to chronic liver disease. In our efforts towards a second generation HCV NS3 serine protease inhibitor with improved profile, we have undertaken SAR studies in various regions of Boceprevir including P2. Herein, we report the synthesis and structure-activity relationship studies of inhibitors with (S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid 2 as P2 substituent replacing the (1R,2S,5S)-6,6-dimethyl 3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The systematic investigation led to the discovery of highly potent inhibitor 25 (K(i)( *)=7nM, EC(90)=30nM) with improved rat exposure of 2.56microM h.
丙型肝炎（HCV）感染是一个全球性的健康危机，可导致慢性肝病。为了研发第二代丙型肝炎 NS3 丝氨酸蛋白酶抑制剂，我们对 Boc 蛋白酶抑制剂的各个区域（包括 P2 区域）进行了构效关系研究。本文报告了（S）-1,4-二硫杂-7-氮杂螺[4.4]壬烷-8-羧酸 2 取代（1R,2S,5S）-6,6-二甲基 3-氮杂双环[3.1.0]己烷-2-羧酸作为 P2 取代基的抑制剂的合成和构效关系研究。系统的研究发现了具有高活性的抑制剂 25（K(i)( *)=7nM，EC(90)=30nM），其大鼠暴露量提高到 2.56microM h。
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