Design, synthesis, and anti-inflammatory properties of orally active 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine p38α mitogen-activated protein kinase inhibitors

John Hynes, Alaric J. Dyckman, Shuqun Lin, Stephen T. Wrobleski, Hong Wu, Kathleen M. Gillooly, Steven B. Kanner, Herinder Lonial, Derek Loo, Kim W. McIntyre, Sidney Pitt, Ren Shen Ding, David J. Shuster, Xiao Xia Yang, Rosemary Zhang, Kamelia Behnia, Hongjian Zhang, Punit H. Marathe, Arthur M. Doweyko, John S. TokarskiJohn S. Sack, Matthew Pokross, Susan E. Kiefer, John A. Newitt, Joel C. Barrish, John Dodd, Gary L. Schieven, Katerina Leftheris

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

A novel structural class of p38 mitogen-activated protein (MAP) kinase inhibitors consisting of substituted 4-(phenylamino)-pyrrolo[2,1-f][1,2,4] triazines has been discovered. An initial subdeck screen revealed that the oxindole-pyrrolo[2,1-f][1,2,4]triazine lead 2a displayed potent enzyme inhibition (IC50 60 nM) and was active in a cell-based TNFα biosynthesis inhibition assay (IC50 210 nM). Replacement of the C4 oxindole with 2-methyl-5-N-methoxybenzamide aniline 9 gave a compound with superior p38 kinase inhibition (IC50 10 nM) and moderately improved functional inhibition in THP-1 cells. Further replacement of the C6 ester of the pyrrolo[2,1-f][1,2,4]triazine with amides afforded compounds with increased potency, excellent oral bioavailability, and robust efficacy in a murine model of acute inflammation (murine LPS-TNFα). In rodent disease models of chronic inflammation, multiple compounds demonstrated significant inhibition of disease progression leading to the advancement of 2 compounds 11b and 11j into further preclinical and toxicological studies.

Original languageEnglish (US)
Pages (from-to)4-16
Number of pages13
JournalJournal of Medicinal Chemistry
Volume51
Issue number1
DOIs
StatePublished - Jan 10 2008

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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