title: Beta-substituted cyclohexanecarboxamide cathepsin K inhibitors: modification of the 1,2-disubstituted aromatic core.
abstract: Further SAR study around the central 1,2-disubstituted phenyl of the previously disclosed Cat K inhibitor (-)-1 has demonstrated that the solvent exposed P2-P3 linker can be replaced by various 5- or 6-membered heteroaromatic rings. While some potency loss was observed in the 6-membered heteroaromatic series (IC(50)=1 nM for pyridine-linked 4 vs 0.5 nM for phenyl-linked (+/-)-1), several inhibitors showed a significantly decreased shift in the bone resorption functional assay (10-fold for pyridine 4 vs 53-fold for (-)-1). Though this shift was not reduced in the 5-membered heteroaromatic series, potency against Cat K was significantly improved for thiazole 9 (IC(50)=0.2 nM) as was the pharmacokinetic profile of N-methyl pyrazole 10 over our lead compound (-)-1.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, Que., Canada H9H 3L1. joel_robichaud@merck.com
authors.forename: Joël
authors.initials: J
authors.lastname: Robichaud
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Bayly
authors.forename: W Cameron
authors.initials: WC
authors.lastname: Black
authors.forename: Sylvie
authors.initials: S
authors.lastname: Desmarais
authors.forename: Serge
authors.initials: S
authors.lastname: Léger
authors.forename: Frédéric
authors.initials: F
authors.lastname: Massé
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: McKay
authors.forename: Renata M
authors.initials: RM
authors.lastname: Oballa
authors.forename: Julie
authors.initials: J
authors.lastname: Pâquet
authors.forename: M David
authors.initials: MD
authors.lastname: Percival
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Truchon
authors.forename: Gregg
authors.initials: G
authors.lastname: Wesolowski
authors.forename: Sheldon N
authors.initials: SN
authors.lastname: Crane
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000737:chemistry; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D003510:Cyclohexanes; D015853:Cysteine Proteinase Inhibitors; D006841:Hydrocarbons, Aromatic; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K