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-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.
Trieu
V N
VN
Department of Cardiovascular Biology, Hughes Institute, St. Paul, Minnesota 55113, USA. vtrieu@mercury.ih.org
Liu
X P
XP
Chen
C L
CL
Uckun
F M
FM
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology*; D001053:Apolipoproteins / Q000172:deficiency*; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000209:etiology; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004041:Dietary Fats; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004798:Enzymes / Q000097:blood; D006801:Humans; D006937:Hypercholesterolemia / Q000473:pathology; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011799:Quinazolines / Q000097:blood / Q000627:therapeutic use* / Q000633:toxicity; D013997:Time Factors; D014280:Triglycerides / Q000096:biosynthesis* / Q000097:blood
D001053:Apolipoproteins; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D004798:Enzymes; D011799:Quinazolines; D014280:Triglycerides; C404933:WHI P164