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

• Published in: ACS medicinal chemistry letters Vol. 5; no. 1; pp. 78 - 83
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 09-01-2014
• Subjects: Letter; Pgp; fluoro-piperidine; Platelet-derived growth factor; fluorine
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml4003953

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.