Pyrazole-based cathepsin S inhibitors with arylalkynes as P1 binding elements

被引：20

作者：

Ameriks, Michael K. ^{[1
]}

Axe, Frank U. ^{[1
]}

Bembenek, Scott D. ^{[1
]}

Edwards, James P. ^{[1
]}

Gu, Yin ^{[1
]}

Karlsson, Lars ^{[1
]}

Randal, Mike ^{[2
]}

Sun, Siquan ^{[1
]}

Thurmond, Robin L. ^{[1
]}

Zhu, Jian ^{[1
]}

机构：

[1] Johnson & Johnson Pharmaceut Res & Dev LLC, San Diego, CA 92121 USA

[2] Sunesis Pharmaceut, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 21期

关键词：

Cathepsin; Protease; Alkyne; X-ray crystallography; NONCOVALENT INHIBITORS; ARYLAMINOETHYL AMIDES; NEUROPATHIC PAIN; PART; POTENT; IDENTIFICATION; DESIGN; SAR; P3; OPTIMIZATION;

D O I：

10.1016/j.bmcl.2009.09.014

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A crystal structure of 1 bound to a Cys25Ser mutant of cathepsin S helped to elucidate the binding mode of a previously disclosed series of pyrazole-based CatS inhibitors and facilitated the design of a new class of arylalkyne analogs. Optimization of the alkyne and tetrahydropyridine portions of the pharmacophore provided potent CatS inhibitors (IC(50) = 40-300 nM), and an X-ray structure of 32 revealed that the arylalkyne moiety binds in the S1 pocket of the enzyme. (c) 2009 Elsevier Ltd. All rights reserved.

引用

页码：6131 / 6134

页数：4

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