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

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 5; pp. 1524 - 1527
• Main Authors: 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: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.03.2010; Elsevier
• Subjects: 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; Cysteine protease; Osteoporosis; Cathepsin K; Nitrile; Intravenous administration; Enzyme; Cysteine endopeptidases; Oral administration; Enzyme inhibitor; Selectivity; Bioavailability; In vitro; Biological activity; Optimization; Peptidases; In vivo; Binding mode; Hydrolases; Pyrimidine derivatives; Fluorine Organic compounds; Pharmacokinetics; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.01.100

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%.