Pyrrolidine-5,5-trans-lactams.: 1.: Synthesis and incorporation into inhibitors of hepatitis C virus NS3/4A protease

被引：24

作者：

Andrews, DM ^{[1
]}

Carey, SJ ^{[1
]}

Chaignot, H ^{[1
]}

Coomber, BA ^{[1
]}

Gray, NM ^{[1
]}

Hind, SL ^{[1
]}

Jones, PS ^{[1
]}

Mills, G ^{[1
]}

Robinson, JE ^{[1
]}

Slater, MJ ^{[1
]}

机构：

[1] GlaxoSmithKline Med Res Ctr, Stevenage SG1 2NY, Herts, England

来源：

ORGANIC LETTERS | 2002年 / 4卷 / 25期

关键词：

D O I：

10.1021/ol027013x

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

[GRAPHICS] In this, the first of two letters, we outline the use of the pyrrolidine-5,5-trans-lactam template to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. The hitherto unreported reaction of the acyl iminium ion precursor 4 with dialkyl-substituted silyl ketene acetals (e.g., 8b) is described. Compound 12b, with a spirocyclobutyl P1 substituent and a cyclopropylacyl substituent on the lactam nitrogen, has a k(obs)/l of 400 M-1 s(-1) and demonstrates activity in a replicon cell-based surrogate HCV assay.

引用

页码：4475 / 4478

页数：4

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