P 2–P 3 conformationally constrained ketoamide-based inhibitors of cathepsin K

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 15; pp. 3540 - 3546
• Main Authors: Barrett, David G., Boncek, Virginia M., Catalano, John G., Deaton, David N., Hassell, Anne M., Jurgensen, Cynthia H., Long, Stacey T., McFadyen, Robert B., Miller, Aaron B., Miller, Larry R., Payne, J. Alan, Ray, John A., Samano, Vicente, Shewchuk, Lisa M., Tavares, Francis X., Wells-Knecht, Kevin J., Willard, Derril H., Wright, Lois L., Zhou, Hui-Qiang Q.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01-08-2005
• Subjects: Cathepsin K; Cysteine protease inhibitors; Ketoamide; Cysteine protease inhibitors; Cathepsin K; Ketoamide
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.05.062

An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P
2–P
3 linker and modifications to
P
1
′
elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model.
An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P
2-P
3 linker and modifications to
P
1
′
elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model.