title: Beta-substituted cyclohexanecarboxamide: a nonpeptidic framework for the design of potent inhibitors of cathepsin K.
abstract: A new series of nonpeptidic cathepsin K inhibitors that are based on a beta-substituted cyclohexanecarboxamide motif has been developed. Lead optimization yielded compounds with sub-nanomolar potency and exceptional selectivity profiles against cathepsins B, L, and S. Use of fluorine atoms to block metabolism on the cyclohexyl ring led to compounds with excellent pharmacokinetic properties. Considering the well-established role of cathepsin K in osteoclast-mediated bone turnover, compounds such as (-)-34a (hrab Cat K IC(50) 0.28 nM; >800-fold selectivity vs Cat B, L, and S; PK data in dogs: F 55%, t(1/2) = 15 h) exhibit great potential for development as an orally bioavailable therapeutic for treatment of diseases that involve bone loss.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, Quebec, Canada, H9H 3L1. sheldon_crane@merck.com
authors.forename: Sheldon N
authors.initials: SN
authors.lastname: Crane
authors.forename: W Cameron
authors.initials: WC
authors.lastname: Black
authors.forename: James T
authors.initials: JT
authors.lastname: Palmer
authors.forename: Dana E
authors.initials: DE
authors.lastname: Davis
authors.forename: Eduardo
authors.initials: E
authors.lastname: Setti
authors.forename: Joel
authors.initials: J
authors.lastname: Robichaud
authors.forename: Julie
authors.initials: J
authors.lastname: Paquet
authors.forename: Renata M
authors.initials: RM
authors.lastname: Oballa
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Bayly
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: McKay
authors.forename: John R
authors.initials: JR
authors.lastname: Somoza
authors.forename: Natalie
authors.initials: N
authors.lastname: Chauret
authors.forename: Carmai
authors.initials: C
authors.lastname: Seto
authors.forename: John
authors.initials: J
authors.lastname: Scheigetz
authors.forename: Greg
authors.initials: G
authors.lastname: Wesolowski
authors.forename: Frederic
authors.initials: F
authors.lastname: Massé
authors.forename: Sylvie
authors.initials: S
authors.lastname: Desmarais
authors.forename: Marc
authors.initials: M
authors.lastname: Ouellet
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000607:Aminoacetonitrile / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D006207:Half-Life; D008297:Male; D008958:Models, Molecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D003510:Cyclohexanes; C508997:N-(cyanomethyl)-5,5-dichloro-(4'-(methylthio)-1,1'-biphenyl-2-yl)cyclohexanecarboxamide; D000607:Aminoacetonitrile; D002403:Cathepsins; D056657:Cathepsin K; C534133:Ctsk protein, rat