INHIBITORS OF CHOLESTEROL BIOSYNTHESIS

胆固醇生物合成抑制剂

基本信息

批准号：
3336912
负责人：
SEIICHI P.T. MATSUDA
金额：
$ 26.35万
依托单位：
RICE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1978
资助国家：
美国
起止时间：
1978-07-01 至 1989-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3336912
关键词：
HMG coA reductases X ray crystallography acetyl coA acetyltransferase adrenocorticotropic hormone antihypercholesterolemic agent apolipoproteins atherosclerosis blood chemistry blood lipid blood lipoprotein blood lipoprotein biosynthesis cholesterol analog corticosteroids density gradient ultracentrifugation drug design /synthesis /production excretion fatty acid metabolism feces analysis gas chromatography gas chromatography mass spectrometry gastrointestinal drug absorption gel electrophoresis gonadotropin releasing factor high density lipoproteins hormone regulation /control mechanism liver metabolism low density lipoprotein mass spectrometry nuclear magnetic resonance spectroscopy postmortem prostacyclins semen small intestines steroid biosynthesis steroid hormone metabolism sterol ester sterols thromboxanes tissue /cell culture triglycerides urinalysis very low density lipoprotein

项目摘要

This research program concerns 15-oxygenated sterols wich have been found to be extraordinarily potent inhibitors of cholesterol synthesis in cultured mammalian cells. Several of these compounds have been shown to have significant hypocholesterolemic activity in rats. In the course of these studies we have obtained rather striking results in preliminary studies in two species of nonhuman primates. The potential importance of these findings, coupled with our continuing fundamental studies of the chemistry and mechanisms of action of these compounds, forms the basis and justification of the renewal request. Briefly, oral administration of 5Alpha-cholest-8(14)-en-3Beta-ol-15-one to baboons caused significant lowering of serum cholesterol levels and of the levels of cholesterol in lipoprotein fraction containing low density lipoproteins (LDL) and very low density lipoproteins (VLDL). Moreover, and elevation of the levels of high density lipoprotein (HDL) cholesterol was described in animals whose initial values of HDL cholesterol were low (or in which the percentage of total serum cholesterol in the HDL fraction was low). Even more striking findings have been observed upon administration of the compound to rhesus monkeys maintained on a diet of moderate cholesterol content. LDL cholesterol and protein levels reduced markedly while HDL cholesterol and protein levels were increased. The HDL profiles were shifted to one in which the HDL2 species dominated. We now seek funds required to extend and confirm these observations in baboons and monkeys and to undertake studies to explore the mechanisms involved in the actions of the Delta8(14)-15-ketosterol in lowering serum cholesterol levels and altering the distribution of cholesterol in lipoproteins in baboons. In addition, we propose to investigate the effects of the inhibitor on serum cholesterol and plasma lipoprotein in rhesus monkeys and most importantly, to study the effect of the compound on coronary artery atherosclerosis. We also propose to extend our studies on the effects, metabolism, and mechanisms of action of 15-oxygenated sterols in cultured mammalian cells and in intact small animals and to continue our studies on the chemistry of 15-oxygenated sterols and their derivatives. The proposal involves a collaborative effort between this laboratory and two NHLBI Primate Resource Centers with additional important collaborations with investigators at a number of other institutions.

该研究计划涉及发现15氧化的固醇是极有效的胆固醇合成抑制剂培养的哺乳动物细胞。这些化合物中的几种已显示为大鼠具有明显的降胆固醇活性。在这些研究我们获得了初步的相当惊人的结果对两种非人类灵长类动物的研究。潜在的重要性这些发现，再加上我们对这些化合物的化学和作用机制，形成了基础和续签请求的理由。简而言之 5alpha-cholest-8（14）-en-3beta-ol-15-one-15-对狒狒造成了显着的显着降低血清胆固醇水平和胆固醇水平含有低密度脂蛋白（LDL）和非常低的脂蛋白分数密度脂蛋白（VLDL）。此外，以及高度的高度在动物中描述了密度脂蛋白（HDL）胆固醇的密度 HDL胆固醇的初始值很低（或者百分比 HDL馏分中的总血清胆固醇低）。更加惊人对化合物的给药进行了发现猴子维持中等胆固醇含量的饮食。 LDL 胆固醇和蛋白质水平明显降低，而HDL胆固醇和蛋白质水平升高。 HDL轮廓转移到 HDL2物种占主导地位。现在，我们寻求需要扩展和确认这些观察的资金狒狒和猴子，并进行研究以探索机制参与Delta8（14）-15-酮固醇降低血清的作用胆固醇水平并改变胆固醇的分布狒狒中的脂蛋白。此外，我们建议调查抑制剂对血清胆固醇和血浆脂蛋白的作用恒河猴，最重要的是，研究化合物对冠状动脉粥样硬化。我们还建议扩展有关影响，代谢和培养的哺乳动物细胞中15氧化固醇的作用机理以及完整的小动物，并继续我们的化学研究 15氧化固醇及其衍生物。该提议涉及该实验室和两个NHLBI灵长类动物资源之间的合作努力中心与研究人员的其他重要合作其他机构的数量。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

14 alpha-Ethyl-5 alpha-cholest-7-ene-3 beta,15 alpha-diol, a potent inhibitor of sterol biosynthesis, has two sites of action in cultured mammalian cells.

14 α-Ethyl-5 α-cholest-7-ene-3 beta,15 α-diol 是甾醇生物合成的有效抑制剂，在培养的哺乳动物细胞中具有两个作用位点。

DOI：
发表时间：
1982
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Pinkerton,FD;Izumi,A;Anderson,CM;Miller,LR;Kisic,A;SchroepferJr,GJ
通讯作者：
SchroepferJr,GJ

Sterol synthesis. A simplified method for the synthesis of 32-oxygenated derivatives of 24,25-dihydrolanosterol.

DOI：
发表时间：
1981-07
期刊：
Journal of lipid research
影响因子：
6.5
作者：
E. Parish;G. Schroepfer
通讯作者：
E. Parish;G. Schroepfer

5 alpha-Cholest-8(14)-en-3 beta-ol-15-one lowers serum cholesterol and induces profound changes in the levels of lipoprotein cholesterol and apoproteins in monkeys fed a diet of moderate cholesterol content.

5 alpha-Cholest-8(14)-en-3 beta-ol-15-one 可降低血清胆固醇，并诱导饲喂中等胆固醇含量饮食的猴子的脂蛋白胆固醇和脱辅基蛋白水平发生深刻变化。

DOI：
10.1073/pnas.81.21.6861
发表时间：
1984
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
SchroepferJr,GJ;Sherrill,BC;Wang,KS;Wilson,WK;Kisic,A;Clarkson,TB
通讯作者：
Clarkson,TB

Inhibitors of sterol synthesis. Synthesis and spectral properties of 3 beta-hydroxy-5 alpha-cholestan-15-one and its 17 beta-epimer and their effects on 3-hydroxy-3-methylglutaryl coenzyme A reductase activity.

甾醇合成抑制剂。