title: Modified acidic nonsteroidal anti-inflammatory drugs as dual inhibitors of mPGES-1 and 5-LOX.
abstract: mPGES-1 is a promising target for development of new anti-inflammatory drugs. We aimed to create mPGES-1 inhibitors by modifying the structure of NSAIDs by replacing the carboxylic acid functionality by sulfonamide moieties. Compounds were also tested for 5-LOX inhibition. The most potent mPGES-1 inhibitor was lonazolac derivative 22 (IC₅₀ = 0.16 μM), while the best 5-LOX inhibition was attained by indomethacin derivative 17 (IC₅₀ = 0.9 μM). Inhibition of COX-1 activity was completely removed.
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University, Tübingen, Auf der Morgenstelle 8, D-72076 Tübingen, Germany.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Elkady
authors.forename: Raimund
authors.initials: R
authors.lastname: Nieß
authors.forename: Anja M
authors.initials: AM
authors.lastname: Schaible
authors.forename: Julia
authors.initials: J
authors.lastname: Bauer
authors.forename: Susann
authors.initials: S
authors.lastname: Luderer
authors.forename: Giulia
authors.initials: G
authors.lastname: Ambrosi
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Laufer
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D007213:Indomethacin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; C017472:lonazolac; D001094:Arachidonate 5-Lipoxygenase; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D007213:Indomethacin