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Södertälje, Sweden

Leclerc P.,Karolinska Institutet | Pawelzik S.-C.,Karolinska Institutet | Idborg H.,Karolinska Institutet | Idborg H.,KDev Exploratory AB | And 7 more authors.
Prostaglandins and Other Lipid Mediators | Year: 2013

Microsomal prostaglandin E synthase (mPGES)-1 inhibition has been proposed as an alternative to cyclooxygenase (COX) inhibition in the treatment of pain and inflammation. This novel approach could potentially mitigate the gastro-intestinal and cardiovascular side effects seen after long-term treatment with traditional non-steroidal anti-inflammatory drugs (NSAIDs) and Coxibs respectively. Several human mPGES-1 inhibitors have been developed in the recent years. However, they were all shown to be considerably less active on rodent mPGES-1, precluding the study of mPGES-1 inhibition in rodent models of inflammation and pain. The aim of this study was to characterize the new mPGES-1 inhibitor compound II, a pyrazolone that has similar potency on rat and human recombinant mPGES-1, in experimental models of inflammation. In cell culture, compound II inhibited PGE2 production in synovial fibroblasts from patients with rheumatoid arthritis (RASF) and in rat peritoneal macrophages. In vivo, compound II was first characterized in the rat air pouch model of inflammation where treatment inhibited intra-pouch PGE2 production. Compound II was also investigated in a rat adjuvant-induced arthritis model where it attenuated both the acute and delayed inflammatory responses. In conclusion, compound II represents a valuable pharmacological tool for the study of mPGES-1 inhibition in rat models. © 2013 Elsevier Inc. All rights reserved.

Novasaid Ab | Date: 2013-06-20

The compounds (R)-1-(5-chloro-6-methyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide and (R)-1-(6-chloro-1-methyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide, as well as pharmaceutically acceptable salts thereof, and a pharmaceutical composition comprising any one of these compounds. The compounds are useful for the treatment and/or prevention of a disorder selected from an inflammatory disease; an autoimmune disease; pain; a breathing disorder; cancer; a cardiovascular disease; a neurodegenerative disease; a bone disease; a disorder due to familial adenomatous polyposis (FAP) condition; overactive bladder; fever; and inflammation-related anorexia.

Spahiu L.,Actar AB | Stenberg P.,Actar AB | Stenberg P.,NovaSAID AB | Larsson C.,Actar AB | And 7 more authors.
Assay and Drug Development Technologies | Year: 2011

Microsomal prostaglandin E 2 synthase-1 (MPGES1) catalyzes the formation of prostaglandin E 2 from the endoperoxide prostaglandin H 2. MPGES1 expression is induced in inflammatory diseases, and this enzyme is regarded as a potential drug target. To aid in the drug discovery effort, a simple method for determination of inhibition mechanism and potency toward both prostaglandin H 2 and glutathione (GSH) has been developed. Using an assay with thiobarbituric acid-based detection, the inhibitory effects of six MPGES1 inhibitors were evaluated. The IC 50 values obtained at three substrate (S) concentrations ([S]K M) were used to estimate inhibition modality and inhibition constant values. This facilitated strategy is a useful and general screening method to evaluate the inhibitory effects of new drug compounds. © Copyright 2011, Mary Ann Liebert, Inc.

Pawelzik S.-C.,Karolinska Institutet | Uda N.R.,Karolinska Institutet | Spahiu L.,Actar AB | Spahiu L.,NovaSAID AB | And 6 more authors.
Journal of Biological Chemistry | Year: 2010

Microsomal prostaglandin E synthase-1 (MPGES1) is induced during an inflammatory reaction from low basal levels by proinflammatory cytokines and subsequently involved in the production of the important mediator of inflammation, prostaglandin E2. Nonsteroidal anti-inflammatory drugs prevent prostaglandin E2 production by inhibiting the upstream enzymes cyclooxygenases 1 and 2. In contrast to these conventional drugs, a new generation of NSAIDs targets the terminal enzyme MPGES1. Some of these compounds potently inhibit human MPGES1 but do not have an effect on the rat orthologue. We investigated this interspecies difference in a rat/human chimeric form of the enzyme as well as in several mutants and identified key residues Thr-131, Leu-135, and Ala-138 in human MPGES1, which play a crucial role as gate keepers for the active site of MPGES1. These residues are situated in transmembrane helix 4, lining the entrance to the cleft between two subunits in the protein trimer, and regulate access of the inhibitor in the rat enzyme. Exchange toward the human residues in rat MPGES1 was accompanied with a gain of inhibitor activity, whereas exchange in human MPGES1 toward the residues found in rat abrogated inhibitor activity. Our data give evidence for the location of the active site at the interface between subunits in the homotrimeric enzyme and suggest a model of how the natural substrate PGH2, or competitive inhibitors of MPGES1, enter the active site via the phospholipid bilayer of the membrane. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Leclerc P.,Karolinska Institutet | Idborg H.,Karolinska Institutet | Idborg H.,KDev Exploratory AB | Idborg H.,NovaSAID AB | And 11 more authors.
Prostaglandins and Other Lipid Mediators | Year: 2013

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. © 2013 Elsevier Ltd. All rights reserved.

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