Structure-based discovery of inhibitors of microsomal prostaglandin E2 synthase-1, 5-lipoxygenase and 5-lipoxygenase-activating protein: promising hits for the development of new anti-inflammatory agents.
J Med Chem
; 54(6): 1565-75, 2011 Mar 24.
Article
em En
| MEDLINE
| ID: mdl-21323313
ABSTRACT
Microsomal prostaglandin E(2) synthase (mPGES)-1 catalyzes the transformation of PGH(2) to PGE(2) that is involved in several pathologies like fever, pain, and inflammatory disorders. To identify novel mPGES-1 inhibitors, we used in silico screening to rapidly direct the synthesis, based on the copper-catalyzed 3 + 2 Huisgen's reaction (click chemistry), of potential inhibitors. We designed 26 new triazole-based compounds in accordance with the pocket binding requirements of human mPGES-1. Docking results, in agreement with ligand efficiency values, suggested the synthesis of 15 compounds that at least in theory were shown to be more efficient in inhibiting mPGES-1. Biological evaluation of these selected compounds has disclosed three new potential anti-inflammatory drugs (I) compound 4 displaying selectivity for mPGES-1 with an IC(50) value of 3.2 µM, (II) compound 20 that dually inhibits 5-lipoxygenase and mPGES-1, and (III) compound 7 apparently acting as 5-lipoxygenase-activating protein inhibitor (IC(50) = 0.4 µM).
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Triazóis
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Araquidonato 5-Lipoxigenase
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Modelos Moleculares
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Inibidores de Lipoxigenase
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Oxirredutases Intramoleculares
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Proteínas Ativadoras de 5-Lipoxigenase
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Inibidores da Proteína Ativadora de 5-Lipoxigenase
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Anti-Inflamatórios
Limite:
Humans
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article