ANTIHYPERLIPIDEMIC PHTHALIMIDE ANALOGUES

本项目的目标是：1)研究化学修饰 邻苯二甲酰亚胺类似物需要哪些基团 最佳降血脂活性：苯基取代的SAR 芳基取代的吡咯烷酮类高邻苯二甲酰亚胺 1-N-邻苯二甲酰亚胺-3-酮缩氨基脲，3-吲唑酮，2-取代-1， 3-吲二酮，2-取代-1-吲哚，4 羟基-2-苯基杂氮-1-酮和N-取代α和 2)对所有新合成的试剂进行评估 他们降低血清胆固醇和甘油三酯水平的能力 啮齿动物；3)检查有效的降血脂亚胺的能力 抑制胆固醇和甘油三酯调节酶活性 肝脏和小肠中的合成；4)探讨其作用模式。 更有效的试剂的作用：邻苯二甲酰亚胺，N，2-丁基咪唑酮，2， 3-二氢二氮杂-1，4-二酮(3-丙酸)，对苯二甲酸和 4-苯基-5，5‘-二甲氧基-2-吡咯烷酮；5)评价 低密度脂蛋白调节肝脏胆固醇合成的研究进展 受体活性，胆固醇酯形成，胆汁酸合成， 排泄和重吸收；6)进行长时间的TEM研究(90天)，以 测定降脂效果、可逆性、对主要器官的损害和 组织(毒性)；7)评价威力的致畸作用 降血脂药。

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.