title: Isosteric replacements for benzothiazoles and optimisation to potent Cathepsin K inhibitors free from hERG channel inhibition.
abstract: The discovery of nitrile compound 4, a potent inhibitor of Cathepsin K (Cat K) with good bioavailability in dog is described. The compound was used to demonstrate target engagement and inhibition of Cat K in an in vivo dog PD model. The margin to hERG ion channel inhibition was deemed too low for a clinical candidate and an optimisation program to find isosteres or substitutions on benzothiazole group led to the discovery of 20, 24 and 27; all three free from hERG inhibition.
authors.affiliation: AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. al.dossetter@astrazeneca.com
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Dossetter
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bowyer
authors.forename: Calum R
authors.initials: CR
authors.lastname: Cook
authors.forename: James J
authors.initials: JJ
authors.lastname: Crawford
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Finlayson
authors.forename: Nicola M
authors.initials: NM
authors.lastname: Heron
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: Philip A
authors.initials: PA
authors.lastname: MacFaul
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
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D056657:Cathepsin K / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004285:Dogs; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009570:Nitriles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D052160:Benzothiazoles; D051638:Ether-A-Go-Go Potassium Channels; D009570:Nitriles; D056657:Cathepsin K