Discovery of a Potent and Selective Noncovalent Linear Inhibitor of the Hepatitis C Virus NS3 Protease (BI 201335)
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- 作者：Montse Llins-Brunet ; Murray D. Bailey ; Nathalie Goudreau ; Punit K. Bhardwaj ; Jose Bordeleau ; Michael Bs ; Yves Bousquet ; Michael G. Cordingley ; Jiamin Duan ; Pat Forgione ; Michel Garneau ; Elise Ghiro ; V
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：September 9, 2010
- 年：2010
- 卷：53
- 期：17
- 页码：6466-6476
- 全文大小：954K
- 年卷期：v.53,no.17(September 9, 2010)
- ISSN：1520-4804
文摘
C-Terminal carboxylic acid containing inhibitors of the NS3 protease are reported. A novel series of linear tripeptide inhibitors that are very potent and selective against the NS3 protease are described. A substantial contribution to the potency of these linear inhibitors arises from the introduction of a C8 substituent on the B-ring of the quinoline moiety found on the P2 of these inhibitors. The introduction of a C8 methyl group results not only in a modest increase in the cell-based potency of these inhibitors but more importantly in a much better pharmacokinetic profile in rats as well. Exploration of C8-substitutions led to the identification of the bromo derivative as the best group at this position, resulting in a significant increase in the cell-based potency of this class of inhibitors. Structure−activity studies on the C8-bromo derivatives ultimately led to the discovery of clinical candidate 29 (BI 201335), a very potent and selective inhibitor of genotype1 NS3 protease with a promising PK profile in rats.