The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K

被引：373

作者：

Gauthier, Jacques Yves ^{[1
]}

Chauret, Nathalie ^{[1
]}

Cromlish, Wanda ^{[1
]}

Desmarais, Sylvie ^{[1
]}

Duong, Le T. ^{[2
]}

Falgueyret, Jean-Pierre ^{[1
]}

Kimmel, Donald B. ^{[2
]}

Lamontagne, Sonia ^{[1
]}

Leger, Serge ^{[1
]}

LeRiche, Tammy ^{[1
]}

Li, Chun Sing ^{[1
]}

Masse, Frederic ^{[1
]}

Mckay, Daniel J. ^{[1
]}

Nicoll-Griffith, Deborah A. ^{[1
]}

Oballa, Renata A. ^{[1
]}

Palmer, James T.

Percival, M. David ^{[1
]}

Riendeau, Denis ^{[1
]}

Robichaud, Joel ^{[1
]}

Rodan, Gideon A. ^{[2
]}

Rodan, Sevgi B. ^{[2
]}

Seto, Carmai ^{[1
]}

Therien, Michel ^{[1
]}

Truong, Vouy-Linh ^{[1
]}

Venuti, Michael C. ^{[3
]}

Wesolowski, Gregg ^{[2
]}

Young, Robert N. ^{[1
]}

Zamboni, Robert ^{[1
]}

Black, W. Cameron ^{[1
]}

机构：

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

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

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 03期

关键词：

cathepsin K; cysteine protease; odanacatib; MK-0822; osteoporosis;

D O I：

10.1016/j.bmcl.2007.12.047

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclinical species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：923 / 928

页数：6

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