Identification of 2-mercaptohexanoic acids as dual inhibitors of 5-lipoxygenase and microsomal prostaglandin E₂ synthase-1

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• 作者：Christine Greiner^a ; ^† ; ; Heiko Zettl^b ; ^† ; ; Andreas Koeberle^a ; Carlo Pergola^c ; Hinnak Northoff^d ; Manfred Schubert-Zsilavecz^b ; Oliver Werz^c ; ^{oliver.werz@uni-jena.de"" rel=""nofollow}
• 关键词：5-Lipoxygenase ; Leukotriene ; Neutrophils ; Inflammation ; Prostaglandin
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2011
• 出版时间：1 June 2011
• 年：2011
• 卷：19
• 期：11
• 页码：3394-3401
• 全文大小：832 K

文摘

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.