title: Identification of a nonbasic, nitrile-containing cathepsin K inhibitor (MK-1256) that is efficacious in a monkey model of osteoporosis.
abstract: Herein, we report on the identification of nonbasic, potent, and highly selective, nitrile-containing cathepsin K (Cat K) inhibitors that are built on our previously identified cyclohexanecarboxamide core structure. Subsequent to our initial investigations, we have found that incorporation of five-membered heterocycles as P2-P3 linkers allowed for the introduction of a methyl sulfone P3-substitutent that was not tolerated in inhibitors containing a six-membered aromatic P2-P3 linker. The combination of a five-membered N-methylpyrazole linker and a methyl sulfone in P3 yielded subnanomolar Cat K inhibitors that were minimally shifted (<10-fold) in our functional bone resorption assay. Issues that arose because of metabolic demethylation of the N-methylpyrazole were addressed through introduction of a 2,2,2-trifluoroethyl substituent. This culminated in the identification of 31 (MK-1256), a potent (Cat K IC 50 = 0.62 nM) and selective (>1100-fold selectivity vs Cat B, L, S, C, H, Z, and V, 110-fold vs Cat F) inhibitor of cathepsin K that is efficacious in a monkey model of osteoporosis.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada, H9H 3L1.
authors.forename: Jöel
authors.initials: J
authors.lastname: Robichaud
authors.forename: W Cameron
authors.initials: WC
authors.lastname: Black
authors.forename: Michel
authors.initials: M
authors.lastname: Thérien
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: Qingping
authors.initials: Q
authors.lastname: Wang
authors.forename: Elise
authors.initials: E
authors.lastname: Isabel
authors.forename: Serge
authors.initials: S
authors.lastname: Léger
authors.forename: Christophe
authors.initials: C
authors.lastname: Mellon
authors.forename: Donald B
authors.initials: DB
authors.lastname: Kimmel
authors.forename: Gregg
authors.initials: G
authors.lastname: Wesolowski
authors.forename: M David
authors.initials: MD
authors.lastname: Percival
authors.forename: Fréderic
authors.initials: F
authors.lastname: Massé
authors.forename: Sylvie
authors.initials: S
authors.lastname: Desmarais
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Falgueyret
authors.forename: Sheldon N
authors.initials: SN
authors.lastname: Crane
mesh_terms: D000818:Animals; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D007700:Kinetics; D008253:Macaca mulatta; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry*; D010024:Osteoporosis / Q000188:drug therapy* / Q000201:enzymology*; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: C532852:5,5-dichloro-N-(1-cyanocyclopropyl)-2-(4-(4-(methylsulfonyl)phenyl)-1-(2,2,2-trifluoroethyl)-1H-pyraazol-3-yl)cyclohexanecarboxamide; D015853:Cysteine Proteinase Inhibitors; D009570:Nitriles; D011720:Pyrazoles; D013450:Sulfones; D002403:Cathepsins; D056657:Cathepsin K; C534133:Ctsk protein, rat