New pyripyropene A derivatives, highly SOAT2-selective inhibitors, improve hypercholesterolemia and atherosclerosis in atherogenic mouse models

The Journal of Pharmacology and Experimental Therapeutics
Taichi OhshiroHiroshi Tomoda

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(-/-)) mice or low-density lipoprotein receptor knockout (Ldlr(-/-)) 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, Apoe(-/-) mice treated with PRD125 (1-,11-O-benzylidene type) at 1 mg/kg/day had significantly lower total plasma cholesterol concentration by 57.9 ± 9.3%; further, the ratio of cholesteryl oleate to cholesteryl linoleate in low-density lipoprotein was lower by 55.6 ± 7.5%, respectively. The hepatic cholesteryl ester levels and SOAT2 activity in th...Continue Reading

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Citations

Feb 3, 2016·Chemical & Pharmaceutical Bulletin·Naoyuki KotokuMotomasa Kobayashi
Feb 3, 2016·Chemical & Pharmaceutical Bulletin·Hiroshi Tomoda
May 28, 2015·Chemistry : a European Journal·Shinichiro FuseTakashi Takahashi
Jun 8, 2018·American Journal of Physiology. Gastrointestinal and Liver Physiology·Adam M LopezStephen D Turley
Oct 28, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·You-Min YingZha-Jun Zhan
May 30, 2020·The Journal of Antibiotics·Taichi OhshiroHiroshi Tomoda

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