|
|||||
|
|
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 |
| Institution: | AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. |
| 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. |
| Keywords: | |
| 本文献已被 PubMed 等数据库收录！ | |