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

被引：24

作者：

Hicken, Erik J. ^{[1
]}

Marmsater, Fred P. ^{[1
]}

Munson, Mark C. ^{[1
]}

Schlachter, Stephen T. ^{[1
]}

Robinson, John E. ^{[1
]}

Allen, Shelley ^{[1
]}

Burgess, Laurence E. ^{[1
]}

DeLisle, Robert Kirk ^{[1
]}

Rizzi, James P. ^{[1
]}

Topalov, George T. ^{[1
]}

Zhao, Qian ^{[1
]}

Hicks, Julie M. ^{[1
]}

Kallan, Nicholas C. ^{[1
]}

Tarlton, Eugene ^{[1
]}

Allen, Andrew ^{[1
]}

Callejo, Michele ^{[1
]}

Cox, April ^{[1
]}

Rana, Sumeet ^{[1
]}

Klopfenstein, Nathalie ^{[1
]}

Woessner, Richard ^{[1
]}

Lyssikatos, Joseph P. ^{[1
]}

机构：

[1] Array BioPharma, Dept Drug Discovery, Boulder, CO 80301 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2014年 / 5卷 / 01期

关键词：

Platelet-derived growth factor; fluoro-piperidine; fluorine; Pgp; RECEPTOR; INHIBITORS; FLUORINATION; ARYLATION; ALPHA;

D O I：

10.1021/ml4003953

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：78 / 83

页数：6

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