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Discovery of AC710, a Globally Selective Inhibitor of Platelet-Derived Growth Factor Receptor-Family Kinases.


ABSTRACT: A series of potent, selective platelet-derived growth factor receptor-family kinase inhibitors was optimized starting from a globally selective lead molecule 4 through structural modifications aimed at improving the physiochemical and pharmacokinetic properties, as exemplified by 18b. Further clearance reduction via per-methylation of the ?-carbons of a solubilizing piperidine nitrogen resulted in advanced leads 22a and 22b. Results from a mouse tumor xenograft, a collagen-induced arthritis model, and a 7 day rat in vivo tolerability study culminated in the selection of compound 22b (AC710) as a preclinical development candidate.

SUBMITTER: Liu G 

PROVIDER: S-EPMC4025831 | biostudies-other | 2012 Dec

REPOSITORIES: biostudies-other

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Discovery of AC710, a Globally Selective Inhibitor of Platelet-Derived Growth Factor Receptor-Family Kinases.

Liu Gang G   Campbell Brian T BT   Holladay Mark W MW   Ford Pulido Julia M JM   Hua Helen H   Gitnick Dana D   Gardner Michael F MF   James Joyce J   Breider Mike A MA   Brigham Daniel D   Belli Barbara B   Armstrong Robert C RC   Treiber Daniel K DK  

ACS medicinal chemistry letters 20120924 12


A series of potent, selective platelet-derived growth factor receptor-family kinase inhibitors was optimized starting from a globally selective lead molecule 4 through structural modifications aimed at improving the physiochemical and pharmacokinetic properties, as exemplified by 18b. Further clearance reduction via per-methylation of the α-carbons of a solubilizing piperidine nitrogen resulted in advanced leads 22a and 22b. Results from a mouse tumor xenograft, a collagen-induced arthritis mode  ...[more]

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