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

…, RB McFadyen, AB Miller, LR Miller, JA Payne…

Index: 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 Jr., Derril H.; Wright, Lois L.; Zhou, Hui-Qiang Q. Bioorganic and Medicinal Chemistry Letters, 2005 , vol. 15, # 15 p. 3540 - 3546

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Citation Number: 34

Abstract

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 P2-P3 linker and modifications to [Formula: see text] elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX ...