【文章名】Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAP-K2) as an Antiinflammatory Target: Discovery and in Vivo Activity of Selective Pyrazolo(1,5-a)pyrimidine Inhibitors Using a Focused Library and Structure-Based Optimization Approach
Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAP-K2) as an Antiinflammatory Target: Discovery and in Vivo Activity of Selective Pyrazolo(1,5-a)pyrimidine Inhibitors Using a Focused Library and Structure-Based Optimization Approach
[摘要]：A novel class of mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) inhibitors was discovered through screening a kinase-focused library. A homology model of MAPKAP-K2 was generated and used to guide the initial SAR studies and to rationalize the observed selectivity over CDK2. An X-ray crystal structure of a compound from the active series bound to crystalline MAPKAP-K2 confirmed the predicted binding mode. This has enabled the discovery of a series of pyrazolo[1,5-a] pyrimidine derivatives showing good in vitro cellular potency as anti-TNF-alpha agents and in vivo efficacy in a mouse model of endotoxin shock.
