Referenced in: none

Automatically associated channels: Kv11.1

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

Authors: 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

Journal, date & volume: Bioorg. Med. Chem. Lett., 2012 Sep 1 , 22, 5563-8

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22858142

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.