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

Morphing structural features of HTS-derived chemotypes led to the discovery of novel 2-cyano-pyrimidine inhibitors of cathepsin K with improved pharmacokinetic profile. Morphing structural features of HTS-derived chemotypes led to the discovery of novel 2-cyano-pyrimidine inhibitors of cathepsin K w...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-03, Vol.20 (5), p.1524-1527
Hauptverfasser:	Rankovic, Zoran, Cai, Jiaqiang, Kerr, Jennifer, Fradera, Xavier, Robinson, John, Mistry, Ashvin, Hamilton, Emma, McGarry, George, Andrews, Fiona, Caulfield, Wilson, Cumming, Iain, Dempster, Maureen, Waller, John, Scullion, Paul, Martin, Iain, Mitchell, Ann, Long, Clive, Baugh, Mark, Westwood, Paul, Kinghorn, Emma, Bruin, John, Hamilton, William, Uitdehaag, Joost, Zeeland, Mario van, Potin, Dominique, Saniere, Laurent, Fouquet, Andre, Chevallier, François, Deronzier, Hortense, Dorleans, Cecile, Nicolai, Eric
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals Binding Sites Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Cathepsin K Cathepsin K - antagonists & inhibitors Cathepsin K - metabolism Cell Line Crystallography, X-Ray Cysteine protease Cysteine Proteinase Inhibitors - chemical synthesis Cysteine Proteinase Inhibitors - chemistry Cysteine Proteinase Inhibitors - pharmacokinetics Drug Design High-Throughput Screening Assays Humans Medical sciences Osteoporosis Pharmacology. Drug treatments Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacokinetics Rats Rats, Sprague-Dawley Structure-Activity Relationship
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Zusammenfassung:	Morphing structural features of HTS-derived chemotypes led to the discovery of novel 2-cyano-pyrimidine inhibitors of cathepsin K with improved pharmacokinetic profile. 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 = 4 nM), >580-fold selectivity over catL and catB, and oral bioavailability in the rat of 52%.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.01.100