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 treatment of inflammatory diseases

Chunjian Liu, James Lin, Stephen T. Wrobleski, Shuqun Lin, John Hynes, Hong Wu, Alaric J. Dyckman, Tianle Li, John Wityak, Kathleen M. Gillooly, Sidney Pitt, Ding Ren Shen, Rosemary F. Zhang, Kim W. McIntyre, Luisa Salter-Cid, David J. Shuster, Hongjian Zhang, Punit H. Marathe, Arthur M. Doweyko, John S. SackSusan E. Kiefer, Kevin F. Kish, John A. Newitt, Murray McKinnon, John H. Dodd, Joel C. Barrish, Gary L. Schieven, Katerina Leftheris

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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 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.

Original languageEnglish (US)
Pages (from-to)6629-6639
Number of pages11
JournalJournal of Medicinal Chemistry
Volume53
Issue number18
DOIs
StatePublished - Sep 23 2010

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

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., ... Leftheris, K. (2010). 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 treatment of inflammatory diseases. Journal of Medicinal Chemistry, 53(18), 6629-6639. https://doi.org/10.1021/jm100540x