Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 5, Issue 1, Pages 78-83Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ml4003953
Keywords
Platelet-derived growth factor; fluoro-piperidine; fluorine; Pgp
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The in silico construction of a PDGFR beta kinase homology model and ensuing medicinal chemistry guided by molecular modeling, led to the identification of potent, small molecule inhibitors of PDGFR Subsequent exploration of structure-activity relationships (SAR) led to the incorporation of a constrained secondary amine to enhance selectivity. Further refinements led to the integration of a fluorine substituted piperidine, which resulted M significant reduction of P-glycoprotein (Pgp) mediated efflux and improved bioavailability. Compound 28 displayed oral exposure in rodents and had a pronounced effect in a pharmacokinetic-pharmacodynamic (PKPD) assay.
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