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San Diego, CA, United States

Liu G.,215 Sorrento Valley Boulevard | Campbell B.T.,215 Sorrento Valley Boulevard | Campbell B.T.,Merck And Co. | Holladay M.W.,215 Sorrento Valley Boulevard | And 16 more authors.
ACS Medicinal Chemistry Letters | Year: 2012

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 model, and a 7 day rat in vivo tolerability study culminated in the selection of compound 22b (AC710) as a preclinical development candidate. © 2012 American Chemical Society.

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