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P2-P3 conformationally constrained ketoamide-based inhibitors of cathepsin K.

Basic Information

ID: ALA1142749

Journal: Bioorg Med Chem Lett

Title: P2-P3 conformationally constrained ketoamide-based inhibitors of cathepsin K.

Authors: Barrett DG, Boncek VM, Catalano JG, Deaton DN, Hassell AM, Jurgensen CH, Long ST, McFadyen RB, Miller AB, Miller LR, Payne JA, Ray JA, Samano V, Shewchuk LM, Tavares FX, Wells-Knecht KJ, Willard DH, Wright LL, Zhou HQ.

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 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.

CiteXplore: 15982880

DOI: 10.1016/j.bmcl.2005.05.062

Patent ID: