Identification of 2-mercaptohexanoic acids as dual inhibitors of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1.
Bioorg Med Chem
; 19(11): 3394-401, 2011 Jun 01.
Article
em En
| MEDLINE
| ID: mdl-21570310
ABSTRACT
5-Lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase (mPGES)-1 are key enzymes in the biosynthesis of leukotrienes and prostaglandin (PG)E2, respectively, and are considered as valuable targets for the treatment of inflammatory diseases. Here, we present the identification of 2-mercaptohexanoic acid derivatives as dual inhibitors of 5-LO and mPGES-1. The lead compound 2(4-(3-biphenyloxypropoxy)phenylthio)hexanoic acid (21) inhibits human 5-LO and mPGES-1 in cell-free assays with an IC50 = 3.5 and 2.2 µM, respectively, and suppresses 5-LO in intact cells with even a higher potency (IC50=0.9 µM). Compound 21 (10 µM) neither significantly inhibited the related 12- or 15-LOs nor cyclooxygenase-1 and -2 or cytosolic phospholipase A2. Based on the selective and potent inhibition of 5-LO and mPGES-1, further assessment of these 2-mercaptohexanoic acids in preclinical models of inflammation are warranted.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Araquidonato 5-Lipoxigenase
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Caproatos
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Inibidores de Lipoxigenase
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Oxirredutases Intramoleculares
Tipo de estudo:
Diagnostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article