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

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.

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