FCE 27677: A novel inhibitor of acyl-CoA:Cholesterol acyltransferase with potent oral hypolipidemic activity

Targeting Acyl-CoA:Diacylglycerol Acyltransferase 1 (DGAT1) with Small Molecule Inhibitors for the Treatment of Metabolic Diseases

“…The average serum concentration of T863 in compound-treated mice at the time of sacrifice was approximately 50 M. BUN, blood urea nitrogen; ALT, alanine aminotransferase; AST, aspartate aminotransferase; NS, not significant. note that none of the inhibitors identified for the closest homolog of DGAT1, ACAT1, are competitive with respect to oleoyl-CoA (22,23). This points to a lack of conservation of this binding pocket in ACAT1 and may explain the selectivity of DGAT1 inhibitors to date with respect to ACAT inhibition (5-7).…”

The Pharmacological Profile of FCE 27677: A Novel ACAT Inhibitor with Potent Hypolipidemic Activity Mediated by Selective Suppression of the Hepatic Secretion of ApoB‐100‐Containing Lipoprotein

“…When mixed with a cholesterol-rich diet and administered to rats at doses ranging between 0.1 and 3 mg/kg/d, FCE 27677 prevented the diet-induced increase of plasma cholesterol in a dose-dependent manner with an ED,, of 0.36 mg/kg/d (9). At the same time, the expected increase of the cholesteryl ester content in the liver was prevented.…”

“…The activity of FCE 27677 was then tested both in the presence of ACAT-containing liposomes of increasing cholesterol-to-phosphatidylcholine ratio, as well as in the presence of increasing concentrations of palmitoyl-CoA. A Dixon plot of the kinetics of the inhibition provided evidence that FCE 27677 acts in a noncompetitive fashion with respect to cholesterol and activated fatty acids, suggesting that the compound interacts directly with a site on the enzyme not involved in substrate binding (9).…”

“…respectively; the liver cholesteryl ester level was decreased by 18%. This pattern of activity could be mimicked only in part by the administration of SO m g k g neomycin, an antibiotic that selectively inhibits cholesterol absorption in the intestine, suggesting that FCE 27677 acted mainly through a mechanism independent from the inhibition of the intestinal enzyme (9).…”