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

We identified a novel organic compound, 4-(3'-bromobenzoyl)-6,7-dimethoxyqu inazoline (compound WHI-P164), as a potent inhibitor of triglyceride (TC) s ynthesis. In an in vitro model of lipid synthesis, WHI-P164 (but not any on e 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 ca used no acute toxicity associated with morbidity or mortality in mice when administered at dose levels ranging from 0.5 to 80 mg/kg. In pharmacokineti c studies in mice, WHI-P164 was rapidly eliminated from plasma with a termi nal elimination half-life of 26.1 +/- 1.3 min after intraperitoneal adminis tration and 33.3 +/- 11.3 min after intravenous administration. Treatment w ith 40 mg/kg WHI-P164 (but not one of three structurally similar control di methoxyquinazoline compounds) administered intraperitoneally once daily for 7 consecutive treatment days blocked the in vivo hepatic TG synthesis in b oth apoE-deficient and wildtype C57B1/6 mice. In apoE-deficient mice mainta ined on a high-fat/high-cholesterol Western diet, WHI-P164 substantially re duced 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 c ells are related events, and inhibiting TG synthesis with WHI-P164 offers a n effective means to treat atherosclerosis.