Discovery of a Novel Class of Imidazo[1,2-a]Pyridines with Potent PDGFR Activity and Oral Bioavailability
ACS Medicinal Chemistry Letters2013Vol. 5(1), pp. 78–83
Citations Over TimeTop 15% of 2013 papers
Erik J. Hicken, Fred P. Marmsater, Mark Munson, Stephen T. Schlachter, John Robinson, Shelley Allen, Laurence E. Burgess, Robert Kirk DeLisle, James P. Rizzi, George Topalov, Qian Zhao, Julie M. Hicks, Nicholas C. Kallan, Eugene Tarlton, Andrew C. Allen, Michele Callejo, April Cox, Sumeet Rana, Nathalie Klopfenstein, Richard Woessner, Joseph P. Lyssikatos
Abstract
The in silico construction of a PDGFRβ 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 in 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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