Arylpyrrolizines as inhibitors of microsomal prostaglandin E2 synthase-1 (mPGES-1) or as dual inhibitors of mPGES-1 and 5-lipoxygenase (5-LOX)

Andy J Liedtke; Peter R W E F Keck; Frank Lehmann; Andreas Koeberle; Oliver Werz; Stefan A Laufer

doi:10.1021/jm900481c

Arylpyrrolizines as inhibitors of microsomal prostaglandin E2 synthase-1 (mPGES-1) or as dual inhibitors of mPGES-1 and 5-lipoxygenase (5-LOX)

J Med Chem. 2009 Aug 13;52(15):4968-72. doi: 10.1021/jm900481c.

Authors

Andy J Liedtke¹, Peter R W E F Keck, Frank Lehmann, Andreas Koeberle, Oliver Werz, Stefan A Laufer

Affiliation

¹ 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

PMID: 19719242
DOI: 10.1021/jm900481c

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology
Intramolecular Oxidoreductases / antagonists & inhibitors*
Lipoxygenase Inhibitors*
Prostaglandin-E Synthases
Pyrroles / chemical synthesis*
Pyrroles / pharmacology
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Lipoxygenase Inhibitors
Pyrroles
Intramolecular Oxidoreductases
Prostaglandin-E Synthases