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

2008; Elsevier BV; Volume: 18; Issue: 3 Linguagem: Inglês

10.1016/j.bmcl.2007.12.047

1464-3405

Jacques Yves Gauthier, Nathalie Chauret, Wanda Cromlish, Sylvie Desmarais, Le T. Duong, Jean‐Pierre Falgueyret, Donald B. Kimmel, Sonia Lamontagne, Serge Léger, Tammy LeRiche, Chun Sing Li, Frédéric Massé, Daniel J. McKay, Deborah A. Nicoll‐Griffith, Renata M. Oballa, James T. Palmer, M. David Percival, Denis Riendeau, Joël Robichaud, Gideon A. Rodan, Sevgi B. Rodan, Carmai Seto, Michel Thérien, Vouy-Linh Truong, Michael C. Venuti, Gregg Wesolowski, Robert N. Young, Robert Zamboni, W. Cameron Black,

Bone Metabolism and Diseases

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.