TMP-153, A NOVEL ACAT INHIBITOR, INHIBITS CHOLESTEROL ABSORPTION AND LOWERS PLASMA-CHOLESTEROL IN RATS AND HAMSTERS

Effects of TMP-153, N-[4-(2-chlorophenyl)-6,7-dimethyl-3-quinolyl]-N'- (2,4-difluorophenyl)urea, on intestinal and hepatic acyl-CoA:choleste rol acyltransferase (ACAT) activities, cholesterol absorption and plas ma cholesterol level in rats and hamsters were studied. TMP-153 has IC 50 values of around 5-10 nM for the hepatic and intestinal ACAT from v arious animals. The most potent inhibition was observed in the intesti nal ACAT from Golden hamsters (IC50 = 2.3 nM). The inhibition mode of TMP-153 was non-competitive for rat intestinal ACAT. TMP-153 inhibited cholesterol esterification both in human colonic adenocarcinoma cells , LS180, and in human hepatoma cells, HepG2 (IC50 = 150 nM and 330 nM, respectively). [C-14]cholesterol and cold cholesterol absorption from the small intestine was markedly inhibited by oral administration of TMP-153 (1 mg/kg) without affecting lymph flow and triglyceride absorp tion. When the compound was given as a dietary admixture, plasma chole sterol was reduced in rats fed a cholesterol diet (ED(50) = 0.25 mg/kg /day), but not in those fed a stock diet. On the other hand, TMP-153 s howed more prominent hypocholesterolemic effect in Golden hamsters fed the stock diet (ED(50) = 0.81 mg/kg/day) than in those fed the choles terol diet (ED(50) = 8.01 mg/kg/day). In hamsters fed the stock diet, TMP-153 markedly decreased the hepatic unesterified cholesterol in add ition to esterified cholesterol content, but did not affect bile flow and the biliary secretion of bile acid and lipids. Different mechanism s for plasma cholesterol lowering by TMP-153 between rats and hamsters was discussed.