HYPOLIPIDEMIC ACTIVITY OF 4-SUBSTITUTED 1,2-DIACYL-1,2,4-TRIAZOLIDINE-3,5-DIONES IN RODENTS

A series of 4-substituted 1,2-diacyl-1,2,4-triazolidine-3,5-diones wer e synthesized and shown to be hypolipidemic in rodents; serum choleste rol and triglyceride levels were significantly reduced following intra peritoneal and oral dosing at 20 mg/kg/day. The hypolipidemic activity of the triazolidine-3,5-diones was improved when R(1) was either a ph enyl or a butyl group. Tissue lipid levels were reduced in the liver, aorta, and small intestine, while fecal lipids, e.g. cholesterol, were increased after 14 days. Very low density lipid cholesterol levels we re reduced but high density lipid cholesterol levels were significantl y increased. It appears that the mode of action of the 1,2-diacyl-1,2, 4-triazolidine-3,5-diones is by the inhibition of the de novo rate lim iting enzyme for lipid synthesis. Enzyme activities suppressed by the agents included ATP-dependent citrate lyase, HMG CoA reductase, acyl C oA cholesterol acyl transferase, acetyl CoA carboxylase, sn-glycerol-3 -phosphate aryl transferase, phosphatidylate phosphohydrolase, and cho lesterol-7 alpha-hydroxylase.