Arylpyrrolizines as inhibitors of microsomal prostaglandin E2 synthase-1 (mPGES-1) or as dual inhibitors of mPGES-1 and 5-lipoxygenase (5-LOX).
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.
Liedtke
Andy J
AJ
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
Keck
Peter R W E F
PR
Lehmann
Frank
F
Koeberle
Andreas
A
Werz
Oliver
O
Laufer
Stefan A
SA
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
D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D011758:Pyrroles; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases