2rg5

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[[Image:2rg5.jpg|left|200px]]<br /><applet load="2rg5" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:2rg5.jpg|left|200px]]
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caption="2rg5, resolution 2.40&Aring;" />
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'''Phenylalanine pyrrolotriazine p38 alpha map kinase inhibitor compound 11B'''<br />
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{{Structure
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|PDB= 2rg5 |SIZE=350|CAPTION= <scene name='initialview01'>2rg5</scene>, resolution 2.40&Aring;
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|SITE=
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|LIGAND= <scene name='pdbligand=279:'>279</scene>
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|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]
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|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])
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}}
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'''Phenylalanine pyrrolotriazine p38 alpha map kinase inhibitor compound 11B'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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2RG5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=279:'>279</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2RG5 OCA].
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2RG5 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2RG5 OCA].
==Reference==
==Reference==
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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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18072718 18072718]
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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:[http://www.ncbi.nlm.nih.gov/pubmed/18072718 18072718]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Mitogen-activated protein kinase]]
[[Category: Mitogen-activated protein kinase]]
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[[Category: transferase]]
[[Category: transferase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:47:00 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 18:35:45 2008''

Revision as of 16:35, 20 March 2008

Image:2rg5.jpg


PDB ID 2rg5

Drag the structure with the mouse to rotate
, 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
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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