title: Arylpyrrolizines as inhibitors of microsomal prostaglandin E2 synthase-1 (mPGES-1) or as dual inhibitors of mPGES-1 and 5-lipoxygenase (5-LOX).
abstract: We synthesized and evaluated inhibitors for the microsomal prostaglandin E2 synthase-1 (mPGES-1), based on the arylpyrrolizine scaffold. In a cell free mPGES-1 assay several "sulfonimides" exceeded our lead ML3000 (3) in potency. The most promising compound, the tolylsulfonimide 11f, revealed an IC50 of 2.1 microM and is equipotent to the literature reference molecule MK886 (1). Selected compounds also potently reduced 5-LOX product formation in intact cells. Inhibition of isolated COX was occasionally remarkably cut down.
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard Karls University Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany. andy.liedtke@uni-tuebingen.de
authors.forename: Andy J
authors.initials: AJ
authors.lastname: Liedtke
authors.forename: Peter R W E F
authors.initials: PR
authors.lastname: Keck
authors.forename: Frank
authors.initials: F
authors.lastname: Lehmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Koeberle
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Laufer
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D016859:Lipoxygenase Inhibitors; D000071876:Prostaglandin-E Synthases; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D011758:Pyrroles; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases