title: Characterization of a human and murine mPGES-1 inhibitor and comparison to mPGES-1 genetic deletion in mouse models of inflammation.
abstract: Microsomal prostaglandin E synthase-1 (mPGES-1) inhibition has been suggested as an alternative to cyclooxygenase (COX) inhibition in the treatment of pain and inflammation. We characterized a selective inhibitor of mPGES-1 activity (compound III) and studied its impact on the prostanoid profile in various models of inflammation. Compound III is a benzoimidazole, which has a submicromolar IC50 in both human and rat recombinant mPGES-1. In cellular assays, it reduced PGE2 production in A549 cells, mouse macrophages and blood, causing a shunt to the prostacyclin pathway in the former two systems. Lastly, we assayed compound III in the air pouch model to verify its impact on the prostanoid profile and compare it to the profile obtained in mPGES-1 k.o. mice. As opposed to mPGES-1 genetic deletion, which attenuated PGE2 production and caused a shunt to the thromboxane pathway, mPGES-1 inhibition with compound III reduced PGE2 production and tended to decrease the levels of other prostanoids.
authors.affiliation: Department of Medicine, Rheumatology Research Unit, Karolinska Institutet, S-171 77 Stockholm, Sweden. Electronic address: Patrick.Leclerc@ki.se.
authors.forename: Patrick
authors.initials: P
authors.lastname: Leclerc
authors.forename: Helena
authors.initials: H
authors.lastname: Idborg
authors.forename: Linda
authors.initials: L
authors.lastname: Spahiu
authors.forename: Charlotte
authors.initials: C
authors.lastname: Larsson
authors.forename: Natalia
authors.initials: N
authors.lastname: Nekhotiaeva
authors.forename: Johan
authors.initials: J
authors.lastname: Wannberg
authors.forename: Patric
authors.initials: P
authors.lastname: Stenberg
authors.forename: Marina
authors.initials: M
authors.lastname: Korotkova
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Jakobsson
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015232:Dinoprostone / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D055786:Gene Knockout Techniques; D006801:Humans; D020128:Inhibitory Concentration 50; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007540:Isonipecotic Acids / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D044262:Prostaglandin H2 / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D051381:Rats; D013929:Thromboxane B2 / Q000378:metabolism
chemical_list: C000590211:1-(1-isopropyl-5,6-dimethyl-1H-benzoimidazol-2-yl)piperidine-4-carboxylic acid cyclopentylamide; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D007540:Isonipecotic Acids; D008070:Lipopolysaccharides; D044262:Prostaglandin H2; D013929:Thromboxane B2; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone
keywords: Air pouch model; Inflammation; Macrophages; Mouse; PGE2; mPGES-1