title: Identification of 2-mercaptohexanoic acids as dual inhibitors of 5-lipoxygenase and microsomal prostaglandin E₂ synthase-1.
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.
authors.affiliation: Department of Pharmaceutical Analytics, Pharmaceutical Institute, Eberhard Karls University Tuebingen, Tuebingen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Greiner
authors.forename: Heiko
authors.initials: H
authors.lastname: Zettl
authors.forename: Andreas
authors.initials: A
authors.lastname: Koeberle
authors.forename: Carlo
authors.initials: C
authors.lastname: Pergola
authors.forename: Hinnak
authors.initials: H
authors.lastname: Northoff
authors.forename: Manfred
authors.initials: M
authors.lastname: Schubert-Zsilavecz
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
mesh_terms: D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry* / Q000378:metabolism; D001555:Benzene Derivatives; D002208:Caproates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000071876:Prostaglandin-E Synthases; D013329:Structure-Activity Relationship
chemical_list: C561102:2-(4-(3-biphenyloxypropoxy)phenylthio)hexanoic acid; D001555:Benzene Derivatives; D002208:Caproates; D016859:Lipoxygenase Inhibitors; C037652:hexanoic acid; D001094:Arachidonate 5-Lipoxygenase; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases