P1 and P3 optimization of novel bicycloproline P2 bearing tetrapeptidyl α-ketoamide based HCV protease inhibitors

被引：27

作者：

Victor, F ^{[1
]}

Lamar, J ^{[1
]}

Snyder, N ^{[1
]}

Yip, Y ^{[1
]}

Guo, DQ ^{[1
]}

Yumibe, N ^{[1
]}

Johnson, RB ^{[1
]}

Wang, QM ^{[1
]}

Glass, JI ^{[1
]}

Chen, SH ^{[1
]}

机构：

[1] Eli Lilly & Co, Lilly Res Lab, Lilly Corp Ctr, Div A, Indianapolis, IN 46285 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 01期

关键词：

D O I：

10.1016/j.bmcl.2003.09.075

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

With the aim of discovering potent and selective HCV protease inhibitors, we synthesized and evaluated a series of Ia based tetrapeptidyl ketoamides with additional modification(s) at P1', P1, and P3 positions. As a result of this effort, we found that replacement of the P3 valine with tert-leucine resulted in the discovery of a series of inhibitors (e.g., 3a, 3c, and 4c) endowed with improved enzyme and/or cellular activity relative to Ia. When dosed to F-344 rats orally at 50 mg/kg, 3a achieved 2.5 x higher liver and plasma exposure in comparison to that detected with 1a. (C) 2003 Elsevier Ltd. All rights reserved.

引用

页码：257 / 261

页数：5

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