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 F
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- 作者：Tomomi Kosugi ; Dale R. Mitchell ; Aiko Fujino ; Minoru Imai ; Mika Kambe ; Shinji Kobayashi ; Hiroaki Makino ; Yohei Matsueda ; Yasuhiro Oue ; Kanji Komatsu ; Keiichiro Imaizumi ; Yuri Sakai ; Satoshi Sugiura ; Osami Takenouchi ; Gen Unoki ; Yuko Yamakoshi ; Vicky Cunliffe ; Julie Frearson ; Richard Gordon ; C. John Harris ; Heidi Kalloo-Hosein ; Joelle Le ; Gita Patel ; Donald J. Simpson ; Brad Sherborne ; Peter S. Thomas ; Naotaka Suzuki ; Midori Takimoto-Kamimura ; Ken-ichiro Kataoka
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：August 9, 2012
- 年：2012
- 卷：55
- 期：15
- 页码：6700-6715
- 全文大小：696K
- 年卷期：v.55,no.15(August 9, 2012)
- ISSN：1520-4804
文摘
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-伪 agents and in vivo efficacy in a mouse model of endotoxin shock.