title: A novel class of nonpeptidic biaryl inhibitors of human cathepsin K.
abstract: A novel series of nonpeptidic biaryl compounds was identified as potent and reversible inhibitors of cathepsin K. The P2-P3 amide bond of a known amino acetonitrile dipeptide 1 was replaced with a phenyl ring, thereby giving rise to this biaryl series that retained potency vs cathepsin K and showed an improved selectivity profile against other cathepsins. Structural modification within this series resulted in the identification of compound (R)-2, a potent human cathepsin K inhibitor (IC(50) = 3 nM) that is selective versus cathepsins B (IC(50) = 3950 nM), L (IC(50) = 3725 nM), and S (IC(50) = 2010 nM). In an in vitro assay involving rabbit osteoclasts and bovine bone, compound (R)-2 inhibited bone resorption with an IC(50) of 95 nM. It was shown that, unlike some peptidic nitrile inhibitors of cysteine proteases, the nitrile moiety of (R)-2 is not converted to the corresponding amide 3 by cathepsin K. This indicates that this class of nonpeptidic nitrile inhibitors is unlikely to be hydrolyzed by cysteine proteases. Furthermore, the inhibition of cathepsin K by compound (R)-2 was shown to be fully reversible and not observably time-dependent. To demonstrate the efficacy of compound (R)-2 in vivo, it was administered to ovariectomized (OVX) rhesus monkeys at 20 mg/kg, po once daily for 8 days, and a urinary marker of bone turnover, N-telopeptide of type I collagen (uNTx), was measured. During the eight-day dosing period, the mean reduction by compound (R)-2 in uNTx was 80% (p < 0.001). This demonstrates that inhibition of cathepsin K leads to an inhibition of this bone resorption marker in OVX rhesus monkeys and strongly suggests that inhibition of cathepsin K is a viable therapeutic approach for the treatment of osteoporosis.
authors.affiliation: Department of Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, Quebec, Canada H9H 3L1. joel_robichaud@merck.com
authors.forename: Joël
authors.initials: J
authors.lastname: Robichaud
authors.forename: Renata
authors.initials: R
authors.lastname: Oballa
authors.forename: Peppi
authors.initials: P
authors.lastname: Prasit
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Falgueyret
authors.forename: M David
authors.initials: MD
authors.lastname: Percival
authors.forename: Gregg
authors.initials: G
authors.lastname: Wesolowski
authors.forename: Sevgi B
authors.initials: SB
authors.lastname: Rodan
authors.forename: Donald
authors.initials: D
authors.lastname: Kimmel
authors.forename: Colena
authors.initials: C
authors.lastname: Johnson
authors.forename: Cliff
authors.initials: C
authors.lastname: Bryant
authors.forename: Shankar
authors.initials: S
authors.lastname: Venkatraman
authors.forename: Eduardo
authors.initials: E
authors.lastname: Setti
authors.forename: Rohan
authors.initials: R
authors.lastname: Mendonca
authors.forename: James T
authors.initials: JT
authors.lastname: Palmer
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000652:urine; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001862:Bone Resorption / Q000378:metabolism; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000737:chemistry; D056657:Cathepsin K; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002417:Cattle; D003094:Collagen / Q000652:urine; D024042:Collagen Type I; D003546:Cysteine Endopeptidases; D006801:Humans; D066298:In Vitro Techniques; D008253:Macaca mulatta; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010052:Ovariectomy; D010455:Peptides / Q000652:urine; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D015415:Biomarkers; D001713:Biphenyl Compounds; D024042:Collagen Type I; C476986:N-(cyanomethyl)-4-methyl-2-(4'-(1-piperazinyl)(1,1'-biphenyl)-3-yl)pentanamide; D009570:Nitriles; D010455:Peptides; D010879:Piperazines; D011480:Protease Inhibitors; C052929:collagen type I trimeric cross-linked peptide; D003094:Collagen; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C028217:cathepsin S; C534130:CTSK protein, human; D056657:Cathepsin K