Discovery of AC710 aGlobally Selective Inhibitorof Platelet-Derived Growth Factor Receptor-Family Kinases

摘要

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.