New Pyripyropene A Derivatives, Highly SOAT2-Selective Inhibitors, Improve Hypercholesterolemia and Atherosclerosis in Atherogenic Mouse Models

Abstract

Sterol O-acyltransferase 2 (SOAT2; also known as ACAT2) is considered as a new therapeutic target for the treatment or prevention of hypercholesterolemia and atherosclerosis. Fungal pyripyropene A (PPPA: 1,7,11-triacyl type), 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 semisynthetic PPPA derivatives, potent, SOAT2-selective, and stable PRDs were selected. In vivo antiatherosclerotic activity of selected PRDs was tested in apolipoprotein E knockout (Apoe 2/2 ) mice or low-density lipoprotein receptor knockout (Ldlr 2/2 ) mice fed a cholesterol-enriched diet (0.2% cholesterol and 21% fat) for 12 weeks. During the PRD treatments, no detrimental side effects were observed. Among three PRDs, Apoe2/2 mice treated with PRD125 (1-,11-O-benzylidene type) at 1 mg/kg/day had significantly lower total plasma cholesterol concentration by 57.9 6 9.3%; further, the ratio of cholesteryl oleate to cholesteryl linoleate in low-density lipoprotein was lower by 55.6 6 7.5%, respectively. The hepatic cholesteryl ester levels and SOAT2 activity in the small intestines and livers of the PRD-treated mice were selectively lowered. The atherosclerotic lesion areas in the aortae of PRD125-treated mice were significantly lower at 62.2 6 13.1%, respectively. Furthermore, both PRDs were also orally active in atherogenic Ldlr 2/2 mice. Among the PRDs tested, PRD125 was the most potent in both mouse models. These results suggest that SOAT2-selective inhibitors such as PRD125 have a high potential as poststatin agents for treatment and/or prevention in patients with atherosclerosis and hypercholesterolemia.

Sterol O-Acyltransferase 2 Contributes to the Yolk Cholesterol Trafficking during Zebrafish Embryogenesis

“…Recent studies indicated that hepatic or intestinal SOAT2 might play a more important role in hypercholesterolemia or atherosclerosis [52, 53]. Accordingly, the studies on SOAT2-specific inhibitors, such as PPPA, revealed the potential of this class of compounds to treat hypercholesterolemia and atherosclerosis [54, 55]. In line with these findings, our results indicated that AVA treatment in the yolk did not, while PPPA treatment did, hindered the yolk consumption measurably in morphometry (Fig 8).…”

Quantitation of the rates of hepatic and intestinal cholesterol synthesis in lysosomal acid lipase-deficient mice before and during treatment with ezetimibe

“…Clearly, in this instance, the co-administration of ezetimibe would be an effective strategy for preventing this from happening and maximizing the benefit of the ERT. Alternatively, a case could be made for blunting re-esterification of this surplus UC within the liver using the new generation of selective SOAT2 inhibitors [63]. All the resources are available for exploring these clinically relevant questions.…”

Design and Synthesis of A‐Ring Simplified Pyripyropene A Analogues as Potent and Selective Synthetic SOAT2 Inhibitors

“…Finally, 7‐ O ‐ p ‐cyanobenzoyl derivative 2 , 1,11‐ O ‐ o ‐methylbenzylidene acetal derivative 3 , and 1,11‐ O ‐ o , o ‐dimethylbenzylidene acetal derivative 4 , which exhibited SOAT2 inhibitory activity and isozyme selectivity greater than those of 1 , have been developed (Figure and Table ). Furthermore, relative to 1 , these derivatives, particularly 3 , exhibited more potent in vivo efficacy …”