title: Design of potent, selective, and orally bioavailable inhibitors of cysteine protease cathepsin k.
abstract: Osteoclast-mediated bone matrix resorption has been attributed to cathepsin K, a cysteine protease of the papain family that is abundantly and selectively expressed in osteoclast. Inhibition of cathepsin K could potentially be an effective method to prevent osteoporosis. Structure-activity studies on a series of reversible ketoamides based inhibitors of cathepsin K have led to identification of potent and selective compounds. Crystallographic studies have given insights into the mode of binding of these inhibitors. A series of ketoamides with varying P1 moieties were first synthesized to find an optimum group that would fit into the S1 subsite of the cysteine protease, cathepsin K. With a desired P1 group in place a variety of heterocyclic analogues in the P' region were synthesized to study their steric and electronic effects. In the process of exploring these P' heterocyclic variations, excellent selectivity was gained over other highly homologous cysteine proteases, including cathepsins L, S, and V. The favorable pharmacokinetic properties of some of these cathepsin K inhibitors in rats make them suitable for evaluation in rodent osteoporosis models. A representative cathepsin K inhibitor was shown to attenuate PTH-stimulated hypercalcemia in the TPTX rat model. These inhibitors provide a viable lead series in the discovery of new therapies for the prevention and treatment of osteoporosis
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. fxt66911@gsk.com
authors.forename: Francis X
authors.initials: FX
authors.lastname: Tavares
authors.forename: Virginia
authors.initials: V
authors.lastname: Boncek
authors.forename: David N
authors.initials: DN
authors.lastname: Deaton
authors.forename: Anne M
authors.initials: AM
authors.lastname: Hassell
authors.forename: Stacey T
authors.initials: ST
authors.lastname: Long
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Miller
authors.forename: Alan A
authors.initials: AA
authors.lastname: Payne
authors.forename: Larry R
authors.initials: LR
authors.lastname: Miller
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Shewchuk
authors.forename: Kevin
authors.initials: K
authors.lastname: Wells-Knecht
authors.forename: Derril H
authors.initials: DH
authors.lastname: Willard
authors.forename: Lois L
authors.initials: LL
authors.lastname: Wright
authors.forename: Hui-Qiang
authors.initials: HQ
authors.lastname: Zhou
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D002118:Calcium / Q000097:blood; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D010024:Osteoporosis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D015853:Cysteine Proteinase Inhibitors; D007659:Ketones; D011994:Recombinant Proteins; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534133:Ctsk protein, rat; D002118:Calcium