3MVM

P38 Alpha Map Kinase complexed with pyrrolotriazine inhibitor 7V

3MVM の概要

• エントリーDOI: 10.2210/pdb3mvm/pdb
• 関連するPDBエントリー: 3MVL
• 分子名称: Mitogen-activated protein kinase 14, 4-{[5-(isoxazol-3-ylcarbamoyl)-2-methylphenyl]amino}-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide (3 entities in total)
• 機能のキーワード: serine/threonine-protein kinase, kinase, transferase, p38 map kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm (By similarity): Q16539
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 85076.93

構造登録者

Sack, J.S. (登録日: 2010-05-04, 公開日: 2010-10-13, 最終更新日: 2024-02-21)

主引用文献

Liu, C.,Lin, J.,Wrobleski, S.T.,Lin, S.,Hynes, J.,Wu, H.,Dyckman, A.J.,Li, T.,Wityak, J.,Gillooly, K.M.,Pitt, S.,Shen, D.R.,Zhang, R.F.,McIntyre, K.W.,Salter-Cid, L.,Shuster, D.J.,Zhang, H.,Marathe, P.H.,Doweyko, A.M.,Sack, J.S.,Kiefer, S.E.,Kish, K.F.,Newitt, J.A.,McKinnon, M.,Dodd, J.H.,Barrish, J.C.,Schieven, G.L.,Leftheris, K.
Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-Methylphenylamino)-5-Methyl-Npropylpyrrolo[1,2-F][1,2,4] Triazine-6-Carboxamide (Bms-582949), a Clinical P38? Map Kinase Inhibitor for the Treatment of Inflammatory Diseases
J.Med.Chem., 53:6629-6639, 2010

PubMed Abstract: The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp(2) character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.

PubMed: 20804198
DOI: 10.1021/jm100540x

実験手法

X-RAY DIFFRACTION (2 Å)