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Design of Cathepsin K Inhibitors for Osteoporosis

[ Vol. 5 , Issue. 16 ]


David N. Deaton and Francis X. Tavares   Pages 1639 - 1675 ( 37 )


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


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


DND or FXT at Department of MedicinalChemistry, GlaxoSmithKline, Research Triangle Park, North Carolina,27709, USA; DND.

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