【文章名】Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), a Clinical p38 alpha MAP Kinase Inhibitor for the Treatment of Inflammatory Diseases
Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), a Clinical p38 alpha MAP Kinase Inhibitor for the Treatment of Inflammatory Diseases
作者
LIU CHUNJIAN; LIN JAMES; WROBLESKI STEPHEN T; LIN SHUQUN; HYNES JOHN JR; WU HONG; DYCKMAN ALARIC J; LI TIANLE; WITYAK JOHN; GILLOOLY KATHLEEN M; PITT SIDNEY; SHEN DING REN; ZHANG ROSEMARY F; MCINTYRE KIM W; SALTERCID LUISA; SHUSTER DAVID J; ZHANG HONGJIAN; MARATHE PUNIT H; DOWEYKO ARTHUR M; SACK JOHN S; KIEFER SUSAN E; KISH KEVIN F; NEWITT JOHN A; MCKINNON MURRAY; DODD JOHN H; BARRISH JOEL C; SCHIEVEN GARY L; LEFTHERIS KATERINA
[摘要]：The discovery and characterization of 7k (BMS-582949), a highly selective p38 alpha, MAP kinase inhibitor that is currently in phase H 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 p38 alpha 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 la in the p38 alpha 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 p38 alpha was confirmed by X-ray crystallographic analysis.
