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| {{STRUCTURE_2rg5| PDB=2rg5 | SCENE= }} | | {{STRUCTURE_2rg5| PDB=2rg5 | SCENE= }} |
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| '''Phenylalanine pyrrolotriazine p38 alpha map kinase inhibitor compound 11B'''
| | ===Phenylalanine pyrrolotriazine p38 alpha map kinase inhibitor compound 11B=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_18072718}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 18072718 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_18072718}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Serine/threonine-protein kinase]] | | [[Category: Serine/threonine-protein kinase]] |
| [[Category: Transferase]] | | [[Category: Transferase]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 16:50:55 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 09:40:59 2008'' |
