Sterol O-acyltransferase 2 (SOAT2) is considered as a potential therapeutic target for the treatment of hypercholesterolemia and atherosclerosis. Fungal pyripyropene A (PPPA), the first SOAT2-selective inhibitor, proved orally active in vivo using atherogenic mouse models. The purpose of the present study was to demonstrate that the PPPA derivatives (PRDs) prove more effective in the mouse models than PPPA. Among 196 semi-synthetic PPPA, potent, SOAT2-selective and stable PRDs were selected. In vivo anti-atherosclerotic activity was tested in apolipoprotein E knockout (Apoe-/-) mice or low density lipoprotein receptor knockout (Ldlr-/-) mice fed a cholesterol-enriched diet. Apoe-/- mice treated with selected PRDs had significantly lower total plasma cholesterol concentration and the ratio of cholesteryl oleate to cholesteryl linoleate in LDL was lower. The hepatic cholesteryl ester levels and SOAT2 activity in the small intestines and livers of the PRD-treated mice were selectively lowered. These effects led to lower atherosclerotic lesion areas in the aortae of PRD-treated mice.
See article at J Pharmacol Exp Ther 2015, 355:297-307.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics