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 (IC 50 60 nM) and was active in a cell-based TNFalpha biosynthesis inhibition assay (IC 50 210 nM). Replacement of the C4 oxindole with 2-methyl-5- N-methoxybenzamide aniline 9 gave a compound with superior p38 kinase inhibition (IC 50 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-TNFalpha). 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Arthritis, Experimental / drug therapy
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Binding Sites
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Crystallography, X-Ray
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Drug Design
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Female
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Humans
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In Vitro Techniques
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / metabolism
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Lipopolysaccharides / pharmacology
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Male
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Mice
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Mice, Inbred BALB C
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Microsomes, Liver / metabolism
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Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase 14 / chemistry
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Models, Molecular
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Pyrroles / chemical synthesis*
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Pyrroles / pharmacokinetics
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Pyrroles / pharmacology
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Rats
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Rats, Inbred Lew
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Structure-Activity Relationship
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Triazines / chemical synthesis*
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Triazines / pharmacokinetics
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Triazines / pharmacology
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / blood
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Lipopolysaccharides
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N-cyclopentyl-4-(2-methyl-5-(methoxycarbamoyl)phenylamino)-5-methylpyrrolo(2,1-f)(1,2,4)triazine-6-carboxamide
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N-ethyl-4-(2-methyl-5-(methoxycarbamoyl)phenylamino)-5-methylpyrrolo(2,1-f)(1,2,4)triazine-6-carboxamide
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Pyrroles
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Triazines
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Tumor Necrosis Factor-alpha
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Mitogen-Activated Protein Kinase 14