Abstract 13138: In vivo Efficacy of PRD017, a New Pyripyropene a Derivative and Highly Potent SOAT2-Selective Inhibitor, in Apolipoprotein E KO Mice

Abstract

Objective: Fungal pyripyropene A (PPPA), the first known selective inhibitor of sterol O-acyltransferase 2 (SOAT2, also known as acyl-CoA:cholesterol acyltransferase 2), proved orally active in atherogenic mouse models. The purpose of the present study was to identify PPPA derivatives that are more effective in vivo in an atherogenic mouse model.

Methods: Over 250 PPPA derivatives having diverse moieties (O-alkyl etc) at C-1, C-7 and C-11, which are involved in inhibitory activity against SOAT2, were prepared from PPPA. SOAT1 and SOAT2 activities were evaluated in cell-based assays using SOAT1- or SOAT2-expressing CHO cells. In vivo anti-atherosclerotic activity of PPPA derivatives was tested in apolipoprotein E knockout (Apoe^-/-) mice fed a Western-type diet (0.2% cholesterol and 21% fat) for 12 weeks.

Results: Among PPPA derivatives, PRD017 having 1-O-acetyl, 7-O-p-cyanobenzoyl and 11-O-acetyl moieties was found to show more potent SOAT2 inhibition (IC₅₀: 0.90 nM) and higher selectivity toward SOAT2 (selectivity index (SI): 4,600) than PPPA (IC₅₀: 70 nM and SI: about 1,000). Treatment of Apoe^-/- mice with PPPA at 1 and 10 mg/kg/day for 12 weeks resulted in little difference of total plasma cholesterol (TPC) levels, while Apoe^-/- mice treated with PRD017 at 1 and 10 mg/kg/day significantly lowered TPC levels by 38±4.4% and 47±4.9 %, respectively. Furthermore, the cholesterol content in the livers of PRD017-treated mice was lowered. The reduction of TPC levels and hepatic cholesterol content was mainly attributed to the lowered cholesterol levels in chylomicron, VLDL and LDL, indicating that hepatic and/or intestinal SOAT2 activity was inhibited by PRD017. Furthermore, the atherosclerotic lesion areas in the aortae and the hearts of PRD017-treated mice were dose-dependently reduced. No toxic effects on the liver and kidney in treated mice were observed during the experiments.

Conclusion: We demonstrate that PRD017 has more potent and selective inhibitory activity against SOAT2 in vitro and more efficient atheroprotective activity than PPPA in vivo. As selective SOAT2 inhibitors, PPPA and its derivatives provide promising leads for the development of a new type of anti-atherosclerotic agents.