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.