SAT0315 INHIBITION OF MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 (MPGES-1) BY GS-248 REDUCES PROSTAGLANDIN E2 BIOSYNTHESIS WHILE INCREASING PROSTACYCLIN IN HUMAN SUBJECTS

Abstract

Background: Microsomal prostaglandin E synthase‐1 (mPGES‐1) catalyzes the formation prostaglandin (PG) E2 from cyclooxygenase derived PGH2 (1, 2). Inhibition of mPGES‐1 leads to reduction of pro‐inflammatory PGE2, while in vessels there is a concomitant increase of vasoprotective prostacyclin (PGI2) via shunting of PGH2 (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. GS‐248 is a potent and selective inhibitor of mPGES‐1 exhibiting sub‐nanomolar IC50 in human whole blood ex vivo. Objectives: To evaluate safety, tolerability, pharmacokinetics and pharmacodynamics of GS‐248. Methods: Healthy males and females (age 18‐73 years) were included in the study. Six cohorts were administrated single oral doses of 1‐300mg GS‐248 (n=36) or placebo (n=12), three cohorts were administered once daily doses of 20‐180mg GS‐248 (n=18) or placebo (n=12) over ten days. In addition, 8 subjects were treated in a separate cohort with 200mg celecoxib bid for ten days. Blood samples were drawn for measurement of GS‐248 exposure and production of PGE2 after LPS incubation ex vivo. The content of PGE2 and PGI2 metabolites was measured in urine. All analyses were performed by LC‐MS/MS. Results: GS‐248 was safe and well tolerated at all tested dose levels. Maximum plasma concentration was achieved 1‐2.5 hours after dosing, and half‐life was about 10 hours. Induced PGE2 formation ex vivo, catalyzed by mPGES‐1, was completely inhibited for 24 hours after a single low dose (40mg) of GS‐248. In urine, GS‐248 dose‐dependently reduced the excretion of PGE2 metabolite by more than 50% whereas the excretion of PGI2 metabolite increased more than twice the baseline levels. In the celecoxib cohort urinary metabolites of both PGE2 and PGI2 were reduced with approx 50%. Conclusion: GS‐248 at investigated oral doses was safe and well tolerated. There was a sustained inhibition of LPS induced PGE2 formation in whole blood. In urine, there was a metabolite shift showing reduced PGE2 and increased PGI2, while celecoxib reduced both PGE2 and PGI2 metabolites. This suggests that selective inhibition of mPGES‐1 results in systemic shunting of PGH2 to PGI2 formation, leading to anti‐inflammatory and vasodilatory effects, while preventing platelet activation. The results warrant further evaluation of GS‐248 in inflammatory conditions with vasculopathies such as Digital Ulcers and Raynaud's Phenomenon in Systemic Sclerosis.