| Autor: |
George T. Topalov, Laurence E. Burgess, Sumeet Rana, Fred P. Marmsater, Robert Kirk Delisle, April Cox, Shelley Allen, Stephen T. Schlachter, Nathalie Klopfenstein, Richard Woessner, Andrew Allen, Michele Callejo, Julie M. Hicks, James P. Rizzi, Robinson John E, Hicken Erik James, Joseph P. Lyssikatos, Nicholas C. Kallan, Qian Zhao, Eugene Tarlton, Mark C. Munson |
| Jazyk: |
angličtina |
| Rok vydání: |
2013 |
| Předmět: |
|
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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