2rg5
From Proteopedia
(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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==Overview== | ==Overview== | ||
| - | A novel structural class of p38 mitogen-activated protein (MAP) kinase | + | 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== | ==About this Structure== | ||
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==Reference== | ==Reference== | ||
| - | Design, | + | 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] |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Mitogen-activated protein kinase]] | [[Category: Mitogen-activated protein kinase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Sack, J | + | [[Category: Sack, J S.]] |
[[Category: 279]] | [[Category: 279]] | ||
[[Category: kinase]] | [[Category: 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 Thu Feb 21 18:47:00 2008'' |
Revision as of 16:47, 21 February 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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