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P2-P3 conformationally constrained ketoamide-based inhibitors of cathepsin K |
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| 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 |
| Institution: | Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. |
| 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. |
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