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.
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