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Biological characterization of new inhibitors of microsomal PGE synthase-1 in preclinical models of inflammation and vascular tone
Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, D2 01, Stockholm, Sweden..
Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, D2 01, Stockholm, Sweden..
Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, D2 01, Stockholm, Sweden..ORCID iD: 0000-0002-0075-6751
Karolinska Univ Hosp, Karolinska Inst, Dept Clin Sci Intervent & Technol, Div Renal Med, Stockholm, Sweden..
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(English)In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381Article in journal (Refereed) Epub ahead of print
Abstract [en]

Background and Purpose Microsomal PGE synthase-1 (mPGES-1), the inducible synthase that catalyses the terminal step in PGE(2) biosynthesis, is of high interest as therapeutic target to treat inflammation. Inhibition of mPGES-1 is suggested to be safer than traditional NSAIDs, and recent data demonstrate anti-constrictive effects on vascular tone, indicating new therapeutic opportunities. However, there is a lack of potent mPGES-1 inhibitors lacking interspecies differences for conducting in vivo studies in relevant preclinical disease models. Experimental Approach Potency was determined based on the reduction of PGE(2) formation in recombinant enzyme assays, cellular assay, human whole blood assay, and air pouch mouse model. Anti-inflammatory properties were assessed by acute paw swelling in a paw oedema rat model. Effect on vascular tone was determined with human ex vivo wire myography. Key Results We report five new mPGES-1 inhibitors (named 934, 117, 118, 322, and 323) that selectively inhibit recombinant human and rat mPGES-1 with IC50 values of 10-29 and 67-250 nM respectively. The compounds inhibited PGE(2) production in a cellular assay (IC50 values 0.15-0.82 mu M) and in a human whole blood assay (IC50 values 3.3-8.7 mu M). Moreover, the compounds blocked PGE(2) formation in an air pouch mouse model and reduced acute paw swelling in a paw oedema rat model. Human ex vivo wire myography analysis showed reduced adrenergic vasoconstriction after incubation with the compounds. Conclusion and Implications These mPGES-1 inhibitors can be used as refined tools in further investigations of the role of mPGES-1 in inflammation and microvascular disease.

Place, publisher, year, edition, pages
WILEY.
National Category
Basic Medicine
Research subject
Pharmacology
Identifiers
URN: urn:nbn:se:uu:diva-401479DOI: 10.1111/bph.14827ISI: 000504584700001PubMedID: 31404942OAI: oai:DiVA.org:uu-401479DiVA, id: diva2:1383438
Available from: 2020-01-08 Created: 2020-01-08 Last updated: 2020-02-05Bibliographically approved

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Wannberg, Johan

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