Referenced in: none

Automatically associated channels: Kv11.1

Title: Optimisation of 2-cyano-pyrimidine inhibitors of cathepsin K: improving selectivity over hERG.

Authors: Zoran Rankovic, Jiaqiang Cai, Jennifer Kerr, Xavier Fradera, John Robinson, Ashvin Mistry, William Finlay, George McGarry, Fiona Andrews, Wilson Caulfield, Iain Cumming, Maureen Dempster, John Waller, Wullie Arbuckle, Mark Anderson, Iain Martin, Ann Mitchell, Clive Long, Mark Baugh, Paul Westwood, Emma Kinghorn, Phil Jones, Joost C M Uitdehaag, Mario van Zeeland, Dominique Potin, Laurent Saniere, Andre Fouquet, François Chevallier, Hortense Deronzier, Cecile Dorleans, Eric Nicolai

Journal, date & volume: Bioorg. Med. Chem. Lett., 2010 Nov 1 , 20, 6237-41

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20843687

Abstract
Several structure-guided optimisation strategies were explored in order to improve the hERG selectivity profile of cathepsin K inhibitor 1, whilst maintaining its otherwise excellent in vitro and in vivo profile. Ultimately, attenuation of clogP and pK(a) properties proved a successful approach and led to the discovery of a potent analogue 23, which, in addition to the desired selectivity over hERG (>1000-fold), displayed a highly attractive overall profile.