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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]

PMID: 24900421

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