Optimisation of 2-cyano-pyrimidine inhibitors of cathepsin K: Improving selectivity over hERG

Autor:	Hortense Deronzier, Cecile Dorleans, John Waller, Laurent Saniere, Andre Fouquet, Fiona Elizabeth Andrews, Mark Baugh, J.C.M. Uitdehaag, George McGarry, Phil Jones, Ann Mitchell, Emma Kinghorn, Eric Nicolai, Wilson Caulfield, Zoran Rankovic, Dominique Potin, Mario van Zeeland, Wullie Arbuckle, Jennifer Kerr, Jiaqiang Cai, Mark Wheaton Anderson, Iain Martin, Maureen Dempster, Ashvin Mistry, François Chevallier, William Finlay, Clive Long, Robinson John E, Xavier Fradera, Paul Westwood, Iain Cumming
Rok vydání:	2010
Předmět:	Models Molecular Molecular model Pyrimidine Stereochemistry Cathepsin K Clinical Biochemistry hERG Pharmaceutical Science Biochemistry Chemical synthesis Structure-Activity Relationship chemistry.chemical_compound Torsades de Pointes In vivo Nitriles Drug Discovery Potassium Channel Blockers Molecular Biology biology Chemistry Organic Chemistry Ether-A-Go-Go Potassium Channels Pyrimidines ROC Curve Enzyme inhibitor Drug Design biology.protein Molecular Medicine Indicators and Reagents Selectivity
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 20:6237-6241
ISSN:	0960-894X
Popis:	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 c log P and p K 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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dbcfb747e700da9944dc50d293047fcc https://doi.org/10.1016/j.bmcl.2010.08.101 Zobrazit plný text záznamu Full Text from ScienceDirect