3MVL

P38 Alpha Map Kinase complexed with pyrrolotriazine inhibitor 7K

Summary for 3MVL

• Entry DOI: 10.2210/pdb3mvl/pdb
• Related: 3MVM
• Descriptor: Mitogen-activated protein kinase 14, 4-{[5-(cyclopropylcarbamoyl)-2-methylphenyl]amino}-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide (3 entities in total)
• Functional Keywords: serine/threonine-protein kinase, kinase, transferase, p38 map kinase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm (By similarity): Q16539
• Total number of polymer chains: 2
• Total formula weight: 85022.97

Authors

Sack, J.S. (deposition date: 2010-05-04, release date: 2010-10-13, Last modification date: 2024-02-21)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.8 Å)