AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
Bioorg Med Chem Lett. 2012 Jun 15;22(12):3879-83. doi: 10.1016/j.bmcl.2012.04.116. Epub 2012 May 2.
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.
已经鉴定出一种新型、有效且选择性的 p38α MAP 激酶喹唑啉酮抑制剂系列。为了解决水溶性差、血浆蛋白结合率高以及苯胺官能团嵌入等问题而进行的修饰，导致了临床候选药物 N-环丙基-4-甲基-3-[6-(4-甲基哌嗪-1-基)-4-氧代喹唑啉-3(4H)-基]苯甲酰胺（AZD6703）的鉴定。通过 X 射线晶体学研究的结合模式的理解来指导优化，这些研究表明随着抑制剂大小的减小，从 DFG“出”到 DFG“入”的转变可以改善整体性质。
