Design, synthesis, and anti-inflammatory properties of orally active 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine p38alpha mitogen-activated protein kinase inhibitors
Bristol-Myers Squibb Pharmaceutical Research Institute
Medical Subject Headings
Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; synthesis; Arthritis, Experimental; Binding Sites; Crystallography, X-Ray; Drug Design; Female; Humans; Leukocytes, Mononuclear; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Microsomes, Liver; Mitogen-Activated Protein Kinase 14; Models, Molecular; Pyrroles; Rats; Rats, Inbred Lew; Structure-Activity Relationship; Triazines; Tumor Necrosis Factor-alpha
Life Sciences | Medicine and Health Sciences
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.
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Citation: J Med Chem. 2008 Jan 10;51(1):4-16. Epub 2007 Dec 12. Link to article on publisher's site
Journal of medicinal chemistry (N-cyclopentyl-4-(2-methyl-5-(methoxycarbamoyl)phenylamino)-5-methylpyrrol o(2,1-f)(1,2,4)triazine-6-carboxamide) (N-ethyl-4-(2-methyl-5-(methoxycarbamoyl)phenylamino)-5-methylpyrrolo(2,1- f)(1,2,4)triazine-6-carboxamide)
Hynes, John; Dyckman, Alaric J.; Lin, Shuqun; Wrobleski, Stephen T.; Wu, Hong; Gillooly, Kathleen M.; Kanner, Steven B.; Lonial, Herinder; Loo, Derek; McIntyre, Kim W.; Pitt, Sidney; Shen, Ding Ren; Shuster, David J.; Yang, Xiaoxia; Zhang, Rosemary F.; Behnia, Kamelia; Zhang, Hongjian; Marathe, Punit H.; Doweyko, Arthur M.; Tokarski, John S.; Sack, John S.; Pokross, Matthew E.; Kiefer, Susan E.; Newitt, John A.; Barrish, Joel C.; Dodd, John H.; Schieven, Gary L.; and Leftheris, Katerina, "Design, synthesis, and anti-inflammatory properties of orally active 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine p38alpha mitogen-activated protein kinase inhibitors" (2007). GSBS Student Publications. 1421.