Design of Cathepsin K Inhibitors for Osteoporosis

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    • Abstract:
      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 S3, S 2, S 1, and S1' subsites with P3, P 2, P 1, and P1' probes have resulted in the identification of potent, selective, orally bioavailable ketoamide-based inhibitors of cathepsin K with demonstrated in vivo efficacy.