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Discovery of a Novel Class of Imidazo[1,2-a]Pyridines with Potent PDGFR Activity and Oral Bioavailability.

Hicken, Erik J; Marmsater, Fred P; Munson, Mark C; Schlachter, Stephen T; Robinson, John E; Allen, Shelley; Burgess, Laurence E; DeLisle, Robert Kirk; Rizzi, James P; Topalov, George T; Zhao, Qian; Hicks, Julie M; Kallan, Nicholas C; Tarlton, Eugene; Allen, Andrew; Callejo, Michele; Cox, April; Rana, Sumeet; Klopfenstein, Nathalie; Woessner, Richard; Lyssikatos, Joseph P.
ACS Med Chem Lett; 5(1): 78-83, 2014 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-24900776
The in silico construction of a PDGFRß 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.
Selo DaSilva