Biological characterization of new inhibitors of microsomal PGE synthase‐1 in preclinical models of inflammation and vascular tone

Abstract

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 IC 50 values of 10-29 and 67-250 nM respectively. The compounds inhibited PGE 2 production in a cellular assay (IC 50 values 0.15-0.82 μM) and in a human whole blood assay (IC 50 values 3.3-8.7 μM). 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.

Anti-Inflammatory Properties of Chemical Probes in Human Whole Blood: Focus on Prostaglandin E2 Production

“…Two of these compounds decreased TXB 2 production, namely trametinib (63% ± 6%, p = 0.02, n = 15) and selumetinib (74% ± 7%, p = 0.02, n = 5). Diclofenac, here used as a positive control for inhibition of prostanoid production, blocked the prostanoid production while selective COX-2 inhibitor NS-398 inhibited only PGE 2 production, in agreement with previously reported data for these compounds in whole blood assay (Larsson et al, 2019). The JAK inhibitor tofacitinib increased both PGE 2 (286% ± 51%, p = 0.01, n = 6) and TXB 2 (169% ± 20%, p = 0.02, n = 6) production.…”

Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE2 biosynthesis by sonlicromanol’s metabolite KH176m

“…However, most of them have exhibited drawbacks, including high lipophilicity and interspecies differences, which has hampered preclinical evaluation of efficacy in routine animal models of inflammation. As such, only a handful of these inhibitors (such as LY3023703) have entered clinical trials [42][43][44] .…”

Sat0315 inhibition of Microsomal Prostaglandin E Synthase-1 (Mpges-1) by Gs-248 Reduces Prostaglandin E2 Biosynthesis While Increasing Prostacyclin in Human Subjects

“…tion of mPGES-1 leads to reduction of pro-inflammatory PGE 2 , while in vessels there is a concomitant increase of vasoprotective prostacyclin (PGI 2 ) via shunting of PGH 2 (3,4) . Apart from relieving symptoms in experimental animal models of inflammation, inhibitors of mPGES-1 cause relaxation of human medium sized arteries (4) and resistance arteries (5) . The prostaglandin profile following mPGES-1 inhibition, explains the anti-inflammatory effects and also opens for the possibility of treating inflammatory diseases with concomitant vasculopathies.…”