Difluoroethylamines as an amide isostere in inhibitors of cathepsin K

被引：19

作者：

Isabel, Elise ^{[1
]}

Mellon, Christophe ^{[1
]}

Boyd, Michael J. ^{[1
]}

Chauret, Nathalie ^{[1
]}

Deschenes, Denis ^{[1
]}

Desmarais, Sylvie ^{[1
]}

Falgueyret, Jean-Pierre ^{[1
]}

Gauthier, Jacques Yves ^{[1
]}

Khougaz, Karine ^{[1
]}

Lau, Cheuk K. ^{[1
]}

Leger, Serge ^{[1
]}

Levorse, Dorothy A. ^{[3
]}

Li, Chun Sing ^{[1
]}

Masse, Frederic ^{[1
]}

Percival, M. David ^{[1
]}

Roy, Bruno ^{[1
]}

Scheigetz, John ^{[1
]}

Therien, Michel ^{[1
]}

Truong, Vouy Linh ^{[1
]}

Wesolowski, Gregg ^{[2
]}

Young, Robert N. ^{[1
]}

Zamboni, Robert ^{[1
]}

Black, W. Cameron ^{[1
]}

机构：

[1] Merck Frosst Ctr Therapeut Res, Quebec City, PQ H9H 3L1, Canada

[2] Merck Res Labs, Dept Bone Biol & Osteoporosis, West Point, PA 19486 USA

[3] Merck Res Labs, Dept Pharmaceut Analyt Chem, Rahway, NJ 07065 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 03期

关键词：

Cathepsin K; Cat K; Difluoroethylamine; log D; pK(a); POTENT;

D O I：

10.1016/j.bmcl.2010.12.070

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The trifluoroethylamine group found in cathepsin K inhibitors like odanacatib can be replaced by a difluoroethylamine group. This change increased the basicity of the nitrogen which positively impacted the log D. This translated into an improved oral bioavailability in pre-clinical species. Difluoroethylamine compounds exhibit a similar potency against cathepsin K and selectivity profile against other cathepsins when compared to trifluoroethylamine analogs. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：920 / 923

页数：4

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