A novel, potent and selective quinazolinone series of inhibitors of p38α 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 ‘out’ to DFG ‘in’ as the inhibitor size was reduced to improve overall properties.

中文翻译：

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的发现Ñ环丙基-4-甲基-3- [6-（4-甲基哌嗪-1-基）-4-氧喹唑啉-3（4 ħ） -基]苯甲酰胺（AZD6703），临床p38αMAP激酶抑制剂为炎性疾病的治疗

已经确定了新颖，有效和选择性的喹唑啉酮系列的p38αMAP激酶抑制剂。为解决水溶性差和血浆蛋白结合力高以及嵌入的苯胺功能性问题而设计的修饰方法导致了临床候选N-环丙基-4-甲基-3- [6-（4-甲基哌嗪-1-基）的鉴定）-4-氧代喹唑啉-3（4 H）-基]苯甲酰胺（AZD6703）。通过了解X射线晶体学研究的结合模式来指导优化，该研究表明，随着抑制剂尺寸的减小，从DFG的“出”转变为DFG的“入”，改善了整体性能。