Document Report Card

ID: ALA1138774

Journal: J Med Chem

Title: Potent and selective ketoamide-based inhibitors of cysteine protease, cathepsin K.

Authors: Tavares FX, Deaton DN, Miller AB, Miller LR, Wright LL, Zhou HQ.

Abstract: Cathepsin K, a lysosomal cysteine protease of the papain superfamily, is abundantly and selectively expressed in osteoclasts, suggesting that this enzyme is crucial for bone resorption. Prevention of osteoclast-mediated bone resorption via inhibition of cathepsin K could be an effective approach to prevent osteoporosis. Potent and selective reversible ketoamide-based inhibitors have been identified in the present study. Using a known crystal structure of a ketoamide-based inhibitor, information from residues that form the P2/P3 pocket was used in the design of inhibitors that could allow for gains in selectivity and potency. Further, incorporation of P' selective heterocycles, along with the P2/P3 modifications, is also described. These modifications have resulted in potent and selective cathepsin K inhibitors that allow for improvements in their physiochemical properties and represent a viable lead series for the discovery of new therapies for the prevention and treatment of osteoporosis

CiteXplore: 15456248

DOI: 10.1021/jm0400799