Identification of a potent and selective non-basic cathepsin K inhibitor

被引：78

作者：

Li, CS

Deschenes, D

Desmarais, S

Falgueyret, JP

Gauthier, JY

Kimmel, DB

Léger, S

Massé, F

McGrath, ME

McKay, DJ

Percival, MD

Riendeau, D

Rodan, SB

Thérien, M

Truong, VL

Wesolowski, G

Zamboni, R

Black, WC

机构：

[1] Merck Frosst Ctr Therapeut Res, Pointe Claire, PQ H9R 4P8, Canada

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

[3] Celera Genom Inc, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 07期

关键词：

bone resorption; osteoporosis; cysteine protease; cathepsin K; cathepsin K inhibitor; non-basic cathepsin K inhibitor; L-873724;

D O I：

10.1016/j.bmcl.2005.12.071

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Based on our previous study with trifluoroethylamine as a P2-P3 amide isostere of cathepsin K inhibitor, further optimization led to identification of compound 22 (L-873724) as a potent and selective non-basic cathepsin K inhibitor. This compound showed excellent pharmacokinetics and efficacy in an ovariectomized (OVX) rhesus monkey model. The volumes of distribution close to unity were consistent with this compound not being lysosomotropic, which is a characteristic of basic cathepsin K inhibitors. (C) 2006 Elsevier Ltd. All rights reserved.

引用

页码：1985 / 1989

页数：5

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