Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), a Clinical p38α MAP Kinase Inhibitor for the

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• 作者：Chunjian Liu ; James Lin ; Stephen T. Wrobleski ; Shuqun Lin ; John Hynes ; Jr. ; Hong Wu ; Alaric J. Dyckman ; Tianle Li ; John Wityak ; Kathleen M. Gillooly ; Sidney Pitt ; Ding Ren Shen ; Rosemary F. Zhang ; Kim
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：September 23, 2010
• 年：2010
• 卷：53
• 期：18
• 页码：6629-6639
• 全文大小：1006K
• 年卷期：v.53,no.18(September 23, 2010)
• ISSN：1520-4804

文摘

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 sp² 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.