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标题：The Anti-atherogenic Activity of Beauveriolide Derivative BVD327, a Sterol O-Acyltransferase 2-Selective Inhibitor, in Apolipoprotein E Knockout Mice
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作者：Taichi Ohshiro ; Satoshi Imuta ; Ichiro Hijikuro 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2020
卷号：43
期号：6
页码：951-958
DOI：10.1248/bpb.b19-00913
出版社：The Pharmaceutical Society of Japan
摘要：The fungal 13-membered cyclodepsipeptides, beauveriolides I and III, were previously reported to be atheroprotective activity in mouse models via inhibiting sterol O -acyltransferase (SOAT) activity. A total of 149 beauveriolide derivatives (BVDs) synthesized combinatorially were evaluated in in silico absorption, distribution, metabolism and excretion (ADME) analysis and inhibitory activity toward the two SOAT isozymes, SOAT1 and SOAT2. Hence, only 11 BVDs exhibited SOAT2-selective inhibition. Among these, we chose BVD327, which had the highest ADME score, for further evaluation. BVD327 administration (50 mg/kg/d, per os ( p.o. )) significantly decreased atherosclerotic lesions in the aorta and heart (25.4 ± 6.9 and 20.6 ± 2.9%, respectively) in apolipoprotein E knockout ( Apoe −/− ) mice fed a cholesterol-enriched diet (0.2% cholesterol and 21% fat) for 12 weeks. These findings indicate that beauveriolide derivatives can be used as anti-atherosclerotic agents.
关键词：sterol O-acyltransferase 2;beauveriolide;inhibitor;lipid metabolism;atherosclerosis