Treatment of atherosclerosis in apolipoprotein E-deficient mice with 4-(3-Bromobenzoyl)-6,7-dimethoxyquinazoline (WHI-P164), a potent inhibitor of triglyceride synthesis.

Abstract

We identified a novel organic compound, 4-(3'-bromobenzoyl)-6,7-dimethoxyquinazoline (compound WHI-P164), as a potent inhibitor of triglyceride (TG) synthesis. In an in vitro model of lipid synthesis, WHI-P164 (but not any one of the three structurally similar control dimethoxyquinazoline compounds) inhibited the accumulation of TG-rich intracellular lipid droplets in Caco-2 human intestinal cells in a concentration-dependent fashion. WHI-P164 caused no acute toxicity associated with morbidity or mortality in mice when administered at dose levels ranging from 0.5 to 80 mg/kg. In pharmacokinetic studies in mice, WHI-P164 was rapidly eliminated from plasma with a terminal elimination half-life of 26.1 +/- 1.3 min after intraperitoneal administration and 33.3 +/- 11.3 min after intravenous administration. Treatment with 40 mg/kg WHI-P164 (but not one of three structurally similar control dimethoxyquinazoline compounds) administered intraperitoneally once daily for 7 consecutive treatment days blocked the in vivo hepatic TG synthesis in both apoE-deficient and wild-type C57B1/6 mice. In apoE-deficient mice maintained on a high-fat/high-cholesterol Western diet, WHI-P164 substantially reduced the lipid accumulation in the liver after 7 days of treatment and the lipid accumulation in the aorta after 1 month of treatment. Our results in apoE-deficient mice show that lipid accumulation in hepatocytes and foam cells are related events, and inhibiting TG synthesis with WHI-P164 offers an effective means to treat atherosclerosis.

• Authors: V N Trieu, X P Liu, C L Chen, F M Uckun
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 35 Issue 2 Pg. 179-88 (Feb 2000) ISSN: 0160-2446 [Print] United States
• PMID: 10672848 (Publication Type: Journal Article)

Chemical References

• Apolipoproteins
• Dietary Fats
• Enzyme Inhibitors
• Enzymes
• Quinazolines
• Triglycerides
• WHI P164

Topics

• Animals
• Aorta (drug effects, pathology)
• Apolipoproteins (deficiency)
• Arteriosclerosis (drug therapy, etiology)
• Caco-2 Cells
• Chromatography, High Pressure Liquid (methods)
• Dietary Fats
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (therapeutic use)
• Enzymes (blood)
• Humans
• Hypercholesterolemia (pathology)
• Lipid Metabolism
• Liver (drug effects, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Quinazolines (blood, therapeutic use, toxicity)
• Time Factors
• Triglycerides (biosynthesis, blood)