title: Pharmacokinetic benefits of 3,4-dimethoxy substitution of a phenyl ring and design of isosteres yielding orally available cathepsin K inhibitors.
abstract: Rational structure-based design has yielded highly potent inhibitors of cathepsin K (Cat K) with excellent physical properties, selectivity profiles, and pharmacokinetics. Compounds with a 3,4-(CH₃O)₂Ph motif, such as 31, were found to have excellent metabolic stability and absorption profiles. Through metabolite identification studies, a reactive metabolite risk was identified with this motif. Subsequent structure-based design of isoteres culminated in the discovery of an optimized and balanced inhibitor (indazole, 38).
authors.affiliation: AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. crawford.james@gene.com
authors.forename: James J
authors.initials: JJ
authors.lastname: Crawford
authors.forename: Peter W
authors.initials: PW
authors.lastname: Kenny
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bowyer
authors.forename: Calum R
authors.initials: CR
authors.lastname: Cook
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Finlayson
authors.forename: Christine
authors.initials: C
authors.lastname: Heyes
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Highton
authors.forename: Julian A
authors.initials: JA
authors.lastname: Hudson
authors.forename: Anja
authors.initials: A
authors.lastname: Jestel
authors.forename: Stephan
authors.initials: S
authors.lastname: Krapp
authors.forename: Scott
authors.initials: S
authors.lastname: Martin
authors.forename: Philip A
authors.initials: PA
authors.lastname: Macfaul
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: McDermott
authors.forename: Thomas M
authors.initials: TM
authors.lastname: McGuire
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Morley
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Morris
authors.forename: Ken M
authors.initials: KM
authors.lastname: Page
authors.forename: Lyn Rosenbrier
authors.initials: LR
authors.lastname: Ribeiro
authors.forename: Helen
authors.initials: H
authors.lastname: Sawney
authors.forename: Stefan
authors.initials: S
authors.lastname: Steinbacher
authors.forename: Caroline
authors.initials: C
authors.lastname: Smith
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Dossetter
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015195:Drug Design; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001798:Blood Proteins; D003510:Cyclohexanes; D007191:Indazoles; C577931:N-(1-cyanocyclopropyl)-2-((4-(1,3-dimethyl-1H-indazol-5-yl)-2-methylpiperazin-1-yl)carbonyl)cyclohexanecarboxamide; D056657:Cathepsin K