Potent and selective P 2–P 3 ketoamide inhibitors of cathepsin K with good pharmacokinetic properties via favorable P 1′, P 1, and/or P 3 substitutions

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 19; pp. 4897 - 4902
• Main Authors: Barrett, David G., Catalano, John G., Deaton, David N., Hassell, Anne M., Long, Stacey T., Miller, Aaron B., Miller, Larry R., Shewchuk, Lisa M., Wells-Knecht, Kevin J., Willard, Derril H., Wright, Lois L.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 04.10.2004
• Subjects: Cathepsin K; Cysteine protease inhibitor; Ketoamide; Cathepsin K; Ketoamide; Cysteine protease inhibitor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.07.031

A series of ketoamides were synthesized and evaluated for inhibitory activity against cathepsin K. Exploration of the interactions between achiral P 2 substituents and the cysteine protease based on molecular modeling suggestions resulted in potent cathepsin K inhibitors that demonstrated high selectivity versus cathepsins B, H, and L. Subsequent modifications of the P 3, P 1, and P 1′ moieties afforded orally bioavailable inhibitors. A series of ketoamides were synthesized and evaluated for inhibitory activity against cathepsin K. Exploration of the interactions between achiral P 2 substituents and the cysteine protease based on molecular modelling suggestions resulted in potent cathepsin K inhibitors that demonstrated high selectivity versus cathepsins B, H, and L. Subsequent modifications of the P 3, P 1, and P 1′ moieties afforded orally bioavailable inhibitors.