1. Bone-targeted pyrido[2,3-d]pyrimidin-7-ones: potent inhibitors of Src tyrosine kinase as novel antiresorptive agents.
- Author
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Vu CB, Luke GP, Kawahata N, Shakespeare WC, Wang Y, Sundaramoorthi R, Metcalf CA 3rd, Keenan TP, Pradeepan S, Corpuz E, Merry T, Bohacek RS, Dalgarno DC, Narula SS, van Schravendijk MR, Ram MK, Adams S, Liou S, Keats JA, Violette SM, Guan W, Weigele M, and Sawyer TK
- Subjects
- Animals, Bone Resorption drug therapy, Computer Simulation, Dentin metabolism, Drug Design, Durapatite metabolism, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Inhibitory Concentration 50, Osteoclasts drug effects, Pyrimidinones pharmacology, Rabbits, Structure-Activity Relationship, Bone Diseases drug therapy, Bone Resorption prevention & control, Pyrimidinones chemical synthesis, src-Family Kinases antagonists & inhibitors
- Abstract
The design of bone-targeted pyrido[2,3-d]pyrimidin-7-ones as Src tyrosine kinase inhibitors is described. Leveraging SAR from known compounds and using structure-based methods, we were able to rapidly incorporate bone binding components, which maintained, and even increased potency against the target enzyme. Compound 4 displayed a high affinity for hydroxyapatite, a major constituent of bone, and demonstrated antiresoprtive activity in our cell-based assay.
- Published
- 2003
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