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ANTIHYPERLIPIDEMIC PHTHALIMIDE ANALOGUES

抗高血脂邻苯二甲酰亚胺类似物

基本信息

批准号：
3338202
负责人：
IRIS HADDON HALL
金额：
$ 7.62万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
1980
资助国家：
美国
起止时间：
1980-04-01 至 1988-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3338202
关键词：
HMG coA reductases Tangier disease Wolman's disease abetalipoproteinemias acetyl coA carboxylase adenosine triphosphate adipose tissue alkyl group antiatherogenic agent antihyperlipoproteinemic agent blood lipoprotein cachexia cardiovascular disorder chemotherapy cardiovascular pharmacology cholesterol esters chylomicrons clofibrate corticosteroids drug administration routes drug adverse effect drug design /synthesis /production drug screening /evaluation estrogens familial hyperlipoproteinemia type III fatty acid biosynthesis gout heart disorder chemotherapy hormone regulation /control mechanism hypercholesterolemia hyperlipidemia hypertension hypothyroidism inborn lysosomal enzyme disorder insulin ion transport lipid biosynthesis lipolysis low density lipoprotein maleimides membrane permeability mitochondria nephritis nutrition related tag obesity phosphatidate phosphatase phthalimides pyruvates succinates succinimides sweetening agents triacylglycerol lipase triglycerides vascular endothelium permeability very low density lipoprotein

项目摘要

The goals of this project are: 1) to investigate the chemical modification of phthalimide analogues to detemine which moieties are required for optimum hypolipidemic activity: the SAR of phenyl substituted pyrrolidinones, homophthalimide, aryl substituted 1-N-phthalimidobutan-3-one semicarbazones, 3-indazolone, 2-substituted-1, 3-indandiones, 2-substituted-1-indanones, 4 hydroxy-2-phenylphthalazine-1-one and N-substituted Alpha and Beta-phenylglutarimide; 2) to evaluate all newly synthesized agents for their ability to lower serum cholesterol and triglyceride levels in rodents; 3) to examine potent hypolipidemic imides for their ability to inhibit regulatory enzyme activities of cholesterol and triglyceride synthesis in the liver and small intestine; 4) to investigate the mode of action of the more potent agents: phthalimide, N2-butylindazolone, 2, 3-dihydropthalazine-1, 4-dione (3-propionic acid), terephthalic acid and 4-phenyl-5, 5'-dicarbethoxy-2-pyrrolidinone; 5) to assess the effects of the agents on the regulation of liver cholesterol synthesis via LDL receptor activity, cholesterol ester formation, bile acid synthesis, excretion and reabsorption; 6) to conduct long tem studies (90 days) to determine lipid lowering effects, reversibility, damage to major organs and tissue (toxicity); 7) to evaluate teratogenic effects of potent hypolipidemic agents.

该项目的目标是：1）研究化学改性邻苯二甲酰亚胺类似物以确定哪些部分是必需的最佳降血脂活性：苯基取代的 SAR 吡咯烷酮，高邻苯二甲酰亚胺，芳基取代 1-N-邻苯二甲酰亚氨基丁烷-3-酮缩氨基脲，3-吲唑酮，2-取代-1， 3-茚满二酮、2-取代-1-茚满酮、4 羟基-2-苯基酞嗪-1-酮和N-取代的α和 β-苯基戊二酰亚胺； 2）评估所有新合成的试剂他们降低血清胆固醇和甘油三酯水平的能力啮齿类动物； 3) 检查有效的降血脂酰亚胺的能力抑制胆固醇和甘油三酯的调节酶活性在肝脏和小肠中合成； 4）研究模式更有效的药剂的作用：邻苯二甲酰亚胺，N2-丁基吲唑酮，2， 3-二氢酞嗪-1、4-二酮（3-丙酸）、对苯二甲酸和 4-苯基-5, 5'-二乙酯基-2-吡咯烷酮； 5) 评估效果通过LDL调节肝脏胆固醇合成的药物受体活性、胆固醇酯形成、胆汁酸合成、排泄和重吸收； 6）进行长期研究（90天）确定降脂作用、可逆性、对主要器官的损害和组织（毒性）； 7) 评价强效致畸作用降血脂药。