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.
MeSH terms
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Animals
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Bone Diseases / drug therapy*
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Bone Resorption / drug therapy
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Bone Resorption / prevention & control*
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Computer Simulation
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Dentin / metabolism
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Drug Design
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Durapatite / metabolism
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / pharmacology
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Inhibitory Concentration 50
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Osteoclasts / drug effects
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Pyrimidinones / chemical synthesis*
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Pyrimidinones / pharmacology
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Rabbits
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Structure-Activity Relationship
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src-Family Kinases / antagonists & inhibitors*
Substances
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Enzyme Inhibitors
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Pyrimidinones
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Durapatite
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src-Family Kinases