Solid-phase parallel synthesis and SAR of 4-amidofuran-3-one inhibitors of cathepsin S: Effect of sulfonamides P3 substituents on potency and selectivity

被引：14

作者：

Ayesa, Susana ^{[1
]}

Lindquist, Charlotta ^{[1
]}

Agback, Tatiana ^{[1
]}

Benkestock, Kurt ^{[1
]}

Classon, Bjoern ^{[1
]}

Henderson, Ian ^{[1
]}

Hewitt, Ellen ^{[2
]}

Jansson, Katarina ^{[1
]}

Kallin, Anders ^{[1
]}

Sheppard, Dave ^{[2
]}

Samuelsson, Bertil ^{[1
]}

机构：

[1] Medivir AB, SE-14144 Huddinge, Sweden

[2] Medivir UK Ltd, Saffron Walden CB10 1XL, Essex, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2009年 / 17卷 / 03期

关键词：

Serin protease; Inhibitors; Cathepsin K; Cathepsin S; Reversible covalent inhibition; NONCOVALENT INHIBITORS; ARYLAMINOETHYL AMIDES; IDENTIFICATION; DESIGN; ACIDS;

D O I：

10.1016/j.bmc.2008.12.020

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Highly potent and selective 4-amidofuran-3-one inhibitors of cathepsin S are described. The synthesis and structure-activity relationship of a series of inhibitors with a sulfonamide moiety in the P3 position is presented. Several members of the series show sub-nanomolar inhibition of the target enzyme as well as an excellent selectivity pro. le and good cellular potency. Molecular modeling of the most interesting inhibitors describes interactions in the extended S3 pocket and explains the observed selectivity towards cathepsin K. (c) 2008 Elsevier Ltd. All rights reserved.

引用

页码：1307 / 1324

页数：18

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