Abstract 18808: PRD125, a Highly Potent SOAT2 Inhibitor, Attenuates Both Atherosclerosis and Fatty Liver Progression in Cholesterol Diet-fed Rabbit

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Abstract

Objective: Pyripyropene A derivative PRD125 synthesized from fungal pyripyropene A (PPPA), the first known selective inhibitor of sterol O-acyltransferase 2 (SOAT2), proved orally active in atherogenic mouse models. The purpose of the present study was to investigate in vivo efficacy of PRD125, and compare in vivo efficacy between PRD125 and statin, a well-known inhibitor of HMG-CoA reductase or a golden standard of anti-hypercholesterolemia agent, in cholesterol diet-fed rabbits.

Methods: Before drug treatmwent, New Zealand white (NZW) rabbits were fed 0.5% cholesterol diet for 2 weeks. Under the feeding conditions, a drug (PRD125 or atorvastatin) was orally administrated to the cholesterol diet-fed rabbits at doses (1 and/or 10 mg/kg/day) for 12 weeks.

Results: Atorvastatin-treated rabbits (1 mg/kg/day) resulted in subtle decrease total plasma cholesterol (TPC) levels by 27.3±13.8%, while rabbits treated with PRD125 at 1 mg/kg/day significantly lowered TPC levels by 61.0±7.8%. SOAT2 activity in the intestines and livers of PRD125-treated rabbits was significantly lowered, leading to a marked decrease of cholesteryl oleate levels in the plasma cholesteryl esters. The atherosclerotic lesion areas in the aortae of PRD125-treated rabbits were markedly reduced, while atorvastatin-treated rabbit showed no changes of the atherosclerotic lesion area in the aortae when compared with no drug-treated rabbit. Importantly, fatty liver progression caused by the cholesterol diet was dose-dependently blocked by PRD125 treatment, which was confirmed by chemical analysis (decrease of cholesterol and triglyceride levels in the livers) and pathological observation (decrease of lipid accumulation and fibrosis in hepatocytes). Under the same condition atorvastatin showed no effect on the fatty liver progression.

Conclusion: SOAT2-selective inhibitors were found to improve both atherosclerosis and fatty liver progression in cholesterol diet-fed rabbits. Furthermore, PRD125 showed more potent in vivo efficacy than atorvastatin. These findings suggest that PRD125 is not only a promising candidate as a post-statin agent but also a first-in-class candidate as an anti-fatty liver diseases agent.

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