2rg5
From Proteopedia
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|PDB= 2rg5 |SIZE=350|CAPTION= <scene name='initialview01'>2rg5</scene>, resolution 2.40Å | |PDB= 2rg5 |SIZE=350|CAPTION= <scene name='initialview01'>2rg5</scene>, resolution 2.40Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=279:'>279</scene> | + | |LIGAND= <scene name='pdbligand=279:N-ETHYL-4-{[5-(METHOXYCARBAMOYL)-2-METHYLPHENYL]AMINO}-5-METHYLPYRROLO[2,1-F][1,2,4]TRIAZINE-6-CARBOXAMIDE'>279</scene> |
| - | |ACTIVITY= [http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] | + | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </span> |
|GENE= MAPK14, CSBP, CSBP1, CSBP2, CSPB1, MXI2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= MAPK14, CSBP, CSBP1, CSBP2, CSPB1, MXI2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2rg5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2rg5 OCA], [http://www.ebi.ac.uk/pdbsum/2rg5 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2rg5 RCSB]</span> | ||
}} | }} | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Sack, J S.]] | [[Category: Sack, J S.]] | ||
| - | [[Category: 279]] | ||
[[Category: kinase]] | [[Category: kinase]] | ||
[[Category: p38 map kinase]] | [[Category: p38 map kinase]] | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:00:00 2008'' |
Revision as of 02:00, 31 March 2008
| |||||||
| , resolution 2.40Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Gene: | MAPK14, CSBP, CSBP1, CSBP2, CSPB1, MXI2 (Homo sapiens) | ||||||
| Activity: | Mitogen-activated protein kinase, with EC number 2.7.11.24 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
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. 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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