Design of Cathepsin K Inhibitors for Osteoporosis

Author(s): David N. Deaton, Francis X. Tavares

Journal Name: Current Topics in Medicinal Chemistry

Volume 5 , Issue 16 , 2005

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Osteoporosis is a progressive, debilitating bone disease resulting in increased cost and morbidity to the elderly. This review summarizes the therapeutic approaches taken in the treatment of osteoporosis with particular emphasis on cathepsin K inhibitors. Cathepsin K, a cysteine protease predominantly expressed in osteoclasts, is a key player involved in bone matrix degradation. Both genetic ablation and small molecule inhibitor strategies versus cathepsin K have validated the importance of this enzyme in bone resorption. Starting from aldehyde-based leads, this review synopsizes the design of improved small molecule inhibitors by GlaxoWellcome researchers. These efforts involved the evaluation of various warheads, including cyanamides, ketoheterocycles, and ketoamides. Initial structure/activity relationships of aldehyde-based inhibitors proved useful in the design of ketoamide-based cathepsin K inhibitors. Further exploration of

Keywords: Bisphosphonates, osteoprotegerin, anti-resorptive therapy, bone mineral density (BMD), elastolytic activity, semicarbazones, ketoheterocycles

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Article Details

Year: 2005
Page: [1639 - 1675]
Pages: 37
DOI: 10.2174/156802605775009676
Price: $65

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