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 language | English (US) |
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Pages (from-to) | 4-16 |
Number of pages | 13 |
Journal | Journal of Medicinal Chemistry |
Volume | 51 |
Issue number | 1 |
DOIs | |
State | Published - Jan 10 2008 |
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Drug Discovery