title: Discovery of a Novel Class of Imidazo[1,2-a]Pyridines with Potent PDGFR Activity and Oral Bioavailability.
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.
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Hicken
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Fred P
authors.initials: FP
authors.lastname: Marmsater
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Munson
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Schlachter
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Robinson
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Shelley
authors.initials: S
authors.lastname: Allen
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Laurence E
authors.initials: LE
authors.lastname: Burgess
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Robert Kirk
authors.initials: RK
authors.lastname: DeLisle
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: James P
authors.initials: JP
authors.lastname: Rizzi
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: George T
authors.initials: GT
authors.lastname: Topalov
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Hicks
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Kallan
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Eugene
authors.initials: E
authors.lastname: Tarlton
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Allen
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Michele
authors.initials: M
authors.lastname: Callejo
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: April
authors.initials: A
authors.lastname: Cox
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Sumeet
authors.initials: S
authors.lastname: Rana
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Klopfenstein
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Woessner
authors.affiliation: Department of Drug Discovery, Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Lyssikatos
keywords: Pgp; Platelet-derived growth factor; fluorine; fluoro-piperidine