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 were synthesized and shown to be hypolipidemic in rodents; serum cholesterol and triglyceride levels were significantly reduced following intraperitoneal and oral dosing at 20 mg/kg/day. The hypolipidemic activity of the triazolidine-3,5-diones was improved when R1 was either a phenyl 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 were reduced but high density lipid cholesterol levels were significantly 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 limiting enzyme for lipid synthesis. Enzyme activities suppressed by the agents included ATP-dependent citrate lyase, HMG CoA reductase, acyl CoA cholesterol acyl transferase, acetyl CoA carboxylase, sn-glycerol-3-phosphate aryl transferase, phosphatidylate phosphohydrolase, and cholesterol-7 alpha-hydroxylase.
Simlot
R
R
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599.
Izydore
R A
RA
Wong
O T
OT
Hall
I H
IH
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005243:Feces / Q000737:chemistry; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D017207:Rats, Sprague-Dawley; D013055:Spectrophotometry, Infrared; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood; D015430:Weight Gain / Q000187:drug effects
D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D008074:Lipoproteins; D014230:Triazoles; D014280:Triglycerides