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 μM 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.