Isosteric replacements for benzothiazoles and optimisation to potent Cathepsin K inhibitors free from hERG channel inhibition

Alexander G Dossetter; Jonathan Bowyer; Calum R Cook; James J Crawford; Jonathan E Finlayson; Nicola M Heron; Christine Heyes; Adrian J Highton; Julian A Hudson; Anja Jestel; Stephan Krapp; Philip A MacFaul; Thomas M McGuire; Andrew D Morley; Jeffrey J Morris; Ken M Page; Lyn Rosenbrier Ribeiro; Helen Sawney; Stefan Steinbacher; Caroline Smith

doi:10.1016/j.bmcl.2012.07.012

Isosteric replacements for benzothiazoles and optimisation to potent Cathepsin K inhibitors free from hERG channel inhibition

Bioorg Med Chem Lett. 2012 Sep 1;22(17):5563-8. doi: 10.1016/j.bmcl.2012.07.012. Epub 2012 Jul 15.

Affiliation

¹ AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. [email protected]

PMID: 22858142
DOI: 10.1016/j.bmcl.2012.07.012

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.

MeSH terms

Animals
Benzothiazoles / chemistry*
Benzothiazoles / metabolism
Benzothiazoles / pharmacokinetics
Benzothiazoles / pharmacology*
Cathepsin K / antagonists & inhibitors*
Cathepsin K / metabolism
Dogs
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
Ether-A-Go-Go Potassium Channels / metabolism
Humans
Microsomes, Liver / metabolism
Models, Molecular
Nitriles / chemistry*
Nitriles / metabolism
Nitriles / pharmacokinetics
Nitriles / pharmacology*
Rats
Structure-Activity Relationship

Substances

Benzothiazoles
Ether-A-Go-Go Potassium Channels
Nitriles
Cathepsin K