Identification of 2-mercaptohexanoic acids as dual inhibitors of 5-lipoxygenase and microsomal prostaglandin E2synthase-1

Christine Greiner, Heiko Zettl, Andreas Koeberle, Carlo Pergola, Hinnak Northoff, Manfred Schubert-Zsilavecz, Oliver Werz, Christine Greiner, Heiko Zettl, Andreas Koeberle, Carlo Pergola, Hinnak Northoff, Manfred Schubert-Zsilavecz, Oliver Werz

Index: Bioorg. Med. Chem. 19(11) , 3394-401, (2011)

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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.Copyright © 2011 Elsevier Ltd. All rights reserved.