Curr Top Med Chem. 2010;10(7):745-51.

Peptidomimetic inhibitors of cathepsin K.

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Merck Frosst Centre for Therapeutic Research, Pointe-Claire-Dorval, Que., Canada. blackc@merck.com

Abstract

Cathepsin K (Cat K) is the primary enzyme involved in Type I collagen degradation in bone resorption. The development of a Cat K inhibitor should provide an effective treatment for osteoporosis. Key components of a clinically viable inhibitor are oral bioavailability, high selectivity over related cathepsins, and a covalent, reversible warhead to bind to the active site cysteine of the enzyme. This article reviews recent advances in the design of inhibitors derived from peptidic leads that contain either a ketone or nitrile electrophile. Three of these compounds have progressed into clinical trials and one, odanacatib (5), is currently in Phase III studies for the treatment of post-menopausal osteoporosis.

PMID:: 20337585; [PubMed - indexed for MEDLINE]

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