Two classes of p38α MAP kinase inhibitors having a common diphenylether core but exhibiting divergent binding modes
- 作者：Enrique L. Michelotti ; Kristofer K. Moffett ; Duyan Nguyen ; Martha J. Kelly ; Rupa Shetty ; Xiaomei Chai ; Katrina Northrop ; Variketta Namboodiri ; Brandon Campbell ; Gary A. Flynn et al.
- 关键词：p38α ; kinase ; MAP kinase ; ATP site ; X-ray ; Crystal
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2005
- 期刊代码：10_0960894x
- 类别：ch
- 出版时间：2005
- 卷：15
- 期：23
- 页码：5274-5279
- 文件大小：174 K
摘要
Two new classes of diphenylether inhibitors of p38α MAP kinase are described. Both chemical classes are based on a common diphenylether core that is identified by simulated fragment annealing as one of the most favored chemotypes within a prominent hydrophobic pocket of the p38α ATP-binding site. In the fully elaborated molecules, the diphenylether moiety acts as an anchor occupying the deep pocket, while polar extensions make specific interactions with either the adenine binding site or the phosphate binding site of ATP. The synthesis, crystallographic analysis, and biological activity of these p38α inhibitors are discussed.