National Center for
3MVM: P38 Alpha Map Kinase Complexed With Pyrrolotriazine Inhibitor 7v
Discovery of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38alpha MAP kinase inhibitor for the treatment of inflammatory diseases
J. Med. Chem. (2010) 53 p.6629-6639
The discovery and characterization of 7k (BMS-582949), a highly selective p38alpha 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 p38alpha 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 p38alpha 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 p38alpha was confirmed by X-ray crystallographic analysis.