title: Design of cathepsin K inhibitors for osteoporosis.
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 S(3), S(2), S(1), and S(1') subsites with P(3), P(2), P(1), and P(1') probes have resulted in the identification of potent, selective, orally bioavailable ketoamide-based inhibitors of cathepsin K with demonstrated in vivo efficacy.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. david.n.deaton@gsk.com
authors.forename: David N
authors.initials: DN
authors.lastname: Deaton
authors.forename: Francis X
authors.initials: FX
authors.lastname: Tavares
mesh_terms: D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use*; D006801:Humans; D010024:Osteoporosis / Q000188:drug therapy*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K