The discovery of N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZD6703), a clinical p38伪 MAP kinase inhibitor for the treatment of inflammatory diseases
A novel, potent and selective quinazolinone series of inhibitors of p38伪 MAP kinase has been identified. Modifications designed to address the issues of poor aqueous solubility and high plasma protein binding as well as embedded aniline functionalities resulted in the identification of a clinical candidate N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZD6703). Optimisation was guided by understanding of the binding modes from X-ray crystallographic studies which showed a switch from DFG 鈥榦ut鈥?to DFG 鈥榠n鈥?as the inhibitor size was reduced to improve overall properties.