Synthesis and hypolipidemic activity of 4‐substituted 1‐acyl‐1,2,4‐triazolidine‐3,5‐diones in rodents

Abstract

A series of 4‐substituted 1‐acyl‐1,2,4‐triazolidine‐3,5‐diones demonstrated potent activity in CF, mice when administered intraperitoneally at 20 mg/kg/day, lowering both serum cholesterol and triglyceride levels significantly. The 4‐(4‐chlorophenyl)‐substituted compounds demonstrated better hypolipidemic activity in rodents than 4‐methoxy‐, 4‐nitro‐, and 4‐t‐butylphenyl substitutions. Aryl and alkyl substitutions rather than benzoyl substitutions at position 4 demonstrated good hypocholesterolemic activity. Selected compounds were examined for the mode of action in rats in which serum cholesterol and triglyceride levels were reduced after administration of 20 mg/kg/day orally; tissue lipids were reduced after 14 days of administration, and bile and fecal lipids were increased by 44–250%. Serum lipoprotein levels were also modulated by the agents, with cholesterol levels in very low density lipoprotein and low density lipoprotein fractions being reduced by 2–57%. Cholesterol levels in the high density lipoprotein fraction were elevated by 94–341%. Activities of mouse hepatic enzymes were suppressed by the agents in a manner that suggested that the compounds interfere with de novo synthesis of lipids. Copyright © 1993 Wiley‐Liss, Inc., A Wiley Company