2rg5
From Proteopedia
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(New page: 200px<br /><applet load="2rg5" size="350" color="white" frame="true" align="right" spinBox="true" caption="2rg5, resolution 2.40Å" /> '''Phenylalanine pyrrol...)
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Revision as of 09:08, 23 January 2008
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Phenylalanine pyrrolotriazine p38 alpha map kinase inhibitor compound 11B
Overview
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.
About this Structure
2RG5 is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Mitogen-activated protein kinase, with EC number 2.7.11.24 Full crystallographic information is available from OCA.
Reference
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., Hynes J Jr, Dyckman AJ, Lin S, Wrobleski ST, Wu H, Gillooly KM, Kanner SB, Lonial H, Loo D, McIntyre KW, Pitt S, Shen DR, Shuster DJ, Yang X, Zhang R, Behnia K, Zhang H, Marathe PH, Doweyko AM, Tokarski JS, Sack JS, Pokross M, Kiefer SE, Newitt JA, Barrish JC, Dodd J, Schieven GL, Leftheris K, J Med Chem. 2008 Jan 10;51(1):4-16. Epub 2007 Dec 12. PMID:18072718
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