Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) as an antiinflammatory target: discovery and in vivo activity of selective pyr...
Basic Information
ID: ALA2163300
Journal: J Med Chem
Title: 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.
Authors: Kosugi T, Mitchell DR, Fujino A, Imai M, Kambe M, Kobayashi S, Makino H, Matsueda Y, Oue Y, Komatsu K, Imaizumi K, Sakai Y, Sugiura S, Takenouchi O, Unoki G, Yamakoshi Y, Cunliffe V, Frearson J, Gordon R, Harris CJ, Kalloo-Hosein H, Le J, Patel G, Simpson DJ, Sherborne B, Thomas PS, Suzuki N, Takimoto-Kamimura M, Kataoka K.
Abstract: 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-α agents and in vivo efficacy in a mouse model of endotoxin shock.
CiteXplore: 22746295
DOI: 10.1021/jm300411k
Patent ID: ┄