Pyrazole-based arylalkyne cathepsin S inhibitors. Part II: Optimization of cellular potency

被引：12

作者：

Ameriks, Michael K. ^{[1
]}

Cai, Hui ^{[1
]}

Edwards, James P. ^{[1
]}

Gebauer, Damara ^{[1
]}

Gleason, Elizabeth ^{[1
]}

Gu, Yin ^{[1
]}

Karlsson, Lars ^{[1
]}

Nguyen, Steven ^{[1
]}

Sun, Siquan ^{[1
]}

Thurmond, Robin L. ^{[1
]}

Zhu, Jian ^{[1
]}

机构：

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

来源：

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

关键词：

Cathepsin; Protease; Invariant chain; Lysosomotropism; NONCOVALENT INHIBITORS; ARYLAMINOETHYL AMIDES; NEUROPATHIC PAIN; SAR; IDENTIFICATION; DESIGN; SELECTIVITY; DISCOVERY; P3; REVERSAL;

D O I：

10.1016/j.bmcl.2009.09.013

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Basic lipophilic substituents dramatically improved the cellular potency of a previously disclosed series of pyrazole-based arylalkyne cathepsin S inhibitors. The incorporation of substituted benzylamines in the para position of the arylalkyne maintained enzymatic activity (hCatS IC(50) = 80-420 nM) and imparted cellular potency (IC(50) = 0.8-4.0 mu M). Further refinement of the morpholine portion of the pharmacophore enabled the identification of bicyclic piperidines with enhanced affinity for CatS (IC(50) = 10-30 nM) and sub-micromolar cellular potency (JY Ii IC(50) = 200-720 nM). (c) 2009 Elsevier Ltd. All rights reserved.

引用

页码：6135 / 6139

页数：5

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