3,4-Disubstituted azetidinones as selective inhibitors of the cysteine protease cathepsin K. Exploring P3 elements for potency and selectivity

• Published in: Bioorganic & medicinal chemistry letters 2005-03, Vol.15 (5), p.1529-1534
• Main Authors: Setti, Eduardo L., Davis, Dana, Janc, James W., Jeffery, Douglas A., Cheung, Harry, Yu, Walter
• Format: Article
• Language: English
• Subjects: Azetidines - chemical synthesis; Azetidines - chemistry; Azetidines - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cathepsin K; Cathepsins - antagonists & inhibitors; Cathepsins - chemistry; Cysteine Proteinase Inhibitors - chemical synthesis; Cysteine Proteinase Inhibitors - chemistry; Cysteine Proteinase Inhibitors - pharmacology; Drug Evaluation, Preclinical; Kinetics; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.12.088

The synthesis of a series of highly potent and selective inhibitors of cathepsin K based on the azetidin-2-one warhead is reported. The synthesis of a series of highly potent and selective inhibitors of cathepsin K based on the 3,4-disubstituted azetidin-2-one warhead is reported. A high degree of potency and selectivity was achieved by introducing a basic nitrogen into the distal part of the P3 element of the molecule. Data from kinetic and mass spectrometry experiments are consistent with the interpretation that compounds of this series transiently acylate the sulfhydrile of cathepsin K.