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.
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.
authors: Teijin Institute for Bio-medical Research,  Teijin Pharma Ltd. , Hino, Tokyo 191-8512, Japan.
authors: Tomomi
authors: T
authors: Kosugi
authors: Dale R
authors: DR
authors: Mitchell
authors: Aiko
authors: A
authors: Fujino
authors: Minoru
authors: M
authors: Imai
authors: Mika
authors: M
authors: Kambe
authors: Shinji
authors: S
authors: Kobayashi
authors: Hiroaki
authors: H
authors: Makino
authors: Yohei
authors: Y
authors: Matsueda
authors: Yasuhiro
authors: Y
authors: Oue
authors: Kanji
authors: K
authors: Komatsu
authors: Keiichiro
authors: K
authors: Imaizumi
authors: Yuri
authors: Y
authors: Sakai
authors: Satoshi
authors: S
authors: Sugiura
authors: Osami
authors: O
authors: Takenouchi
authors: Gen
authors: G
authors: Unoki
authors: Yuko
authors: Y
authors: Yamakoshi
authors: Vicky
authors: V
authors: Cunliffe
authors: Julie
authors: J
authors: Frearson
authors: Richard
authors: R
authors: Gordon
authors: C John
authors: CJ
authors: Harris
authors: Heidi
authors: H
authors: Kalloo-Hosein
authors: Joelle
authors: J
authors: Le
authors: Gita
authors: G
authors: Patel
authors: Donald J
authors: DJ
authors: Simpson
authors: Brad
authors: B
authors: Sherborne
authors: Peter S
authors: PS
authors: Thomas
authors: Naotaka
authors: N
authors: Suzuki
authors: Midori
authors: M
authors: Takimoto-Kamimura
authors: Ken-ichiro
authors: K
authors: Kataoka
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D012772:Shock, Septic / Q000378:metabolism; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D055551:HSP27 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D011743:Pyrimidines; D054852:Small Molecule Libraries; D014409:Tumor Necrosis Factor-alpha; D000099190:MAP-Kinase-Activated Kinase 2