2RG5

Phenylalanine pyrrolotriazine p38 alpha map kinase inhibitor compound 11B

Summary for 2RG5

• Entry DOI: 10.2210/pdb2rg5/pdb
• Descriptor: Mitogen-activated protein kinase 14, N-ethyl-4-{[5-(methoxycarbamoyl)-2-methylphenyl]amino}-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide (3 entities in total)
• Functional Keywords: serine/threonine-protein kinase, kinase, transferase, p38 map kinase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm (By similarity): Q16539
• Total number of polymer chains: 1
• Total formula weight: 42487.42

Authors

Sack, J.S. (deposition date: 2007-10-02, release date: 2008-01-15, Last modification date: 2024-02-21)

Primary citation

Hynes, J.,Dyckman, A.J.,Lin, S.,Wrobleski, S.T.,Wu, H.,Gillooly, K.M.,Kanner, S.B.,Lonial, H.,Loo, D.,McIntyre, K.W.,Pitt, S.,Shen, D.R.,Shuster, D.J.,Yang, X.,Zhang, R.,Behnia, K.,Zhang, H.,Marathe, P.H.,Doweyko, A.M.,Tokarski, J.S.,Sack, J.S.,Pokross, M.,Kiefer, S.E.,Newitt, J.A.,Barrish, J.C.,Dodd, J.,Schieven, G.L.,Leftheris, K.
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
J.Med.Chem., 51:4-16, 2008

PubMed 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.

PubMed: 18072718
DOI: 10.1021/jm7009414

Experimental method

X-RAY DIFFRACTION (2.4 Å)