P2-P3 conformationally constrained ketoamide-based inhibitors of cathepsin K
David G Barrett1, Virginia M Boncek, John G Catalano
1Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
Bioorganic & Medicinal Chemistry Letters
|June 29, 2005
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.


