Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors

Zoran Rankovic; Jiaqiang Cai; Jennifer Kerr; Xavier Fradera; John Robinson; Ashvin Mistry; Emma Hamilton; George McGarry; Fiona Andrews; Wilson Caulfield; Iain Cumming; Maureen Dempster; John Waller; Paul Scullion; Iain Martin; Ann Mitchell; Clive Long; Mark Baugh; Paul Westwood; Emma Kinghorn; John Bruin; William Hamilton; Joost Uitdehaag; Mario van Zeeland; Dominique Potin; Laurent Saniere; Andre Fouquet; François Chevallier; Hortense Deronzier; Cecile Dorleans; Eric Nicolai

doi:10.1016/j.bmcl.2010.01.100

Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors

Bioorg Med Chem Lett. 2010 Mar 1;20(5):1524-7. doi: 10.1016/j.bmcl.2010.01.100. Epub 2010 Jan 25.

Affiliation

¹ Schering-Plough Corporation, Newhouse, Lanarkshire, ML1 5SH Scotland, United Kingdom. [email protected]

PMID: 20149657
DOI: 10.1016/j.bmcl.2010.01.100

Abstract

Morphing structural features of HTS-derived chemotypes led to the discovery of novel 2-cyano-pyrimidine inhibitors of cathepsin K with good pharmacokinetic profiles, for example, compound 20 showed high catK potency (IC(50)=4nM), >580-fold selectivity over catL and catB, and oral bioavailability in the rat of 52%.

MeSH terms

Administration, Oral
Animals
Binding Sites
Cathepsin K / antagonists & inhibitors*
Cathepsin K / metabolism
Cell Line
Crystallography, X-Ray
Cysteine Proteinase Inhibitors / chemical synthesis
Cysteine Proteinase Inhibitors / chemistry*
Cysteine Proteinase Inhibitors / pharmacokinetics
Drug Design
High-Throughput Screening Assays
Humans
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / pharmacokinetics
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship

Substances

Cysteine Proteinase Inhibitors
Pyrimidines
Cathepsin K