Pharmacological Properties of YM17E, an Acyl-CoA:Cholesterol Acyltransferase Inhibitor, and Diarrheal Effect in Beagle Dogs.

Abstract

YM17E (1,3-bis[[1-cycloheptyl-3-(p-dimethylaminophenyl)ureido]methyl]benzene dihydro chloride) was found to be a potent inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT) in rabbit liver and intestine microsomes. Dixon plot analysis revealed that YM17E inhibited microsomal ACAT in a non-competitive manner. YM17E induced a marked decrease in serum cholesterol, especially in non-high density lipoprotein (HDL) fractions, in cholesterol-fed rats and rats fed normal chow. Measurement of bile secretion after oral administration of YM17E in cholesterol-fed rats showed that the drug markedly accelerated the secretion of bile acids and neutral sterols. Furthermore, absorption of [3H]cholesterol from the gut of cholesterol-fed rats was significantly inhibited by YM17E. From these results, the hypocholes terolemic activity of YM17E in these animals resulted from both a decrease in cholesterol absorption from the gut and the stimulation of excretion of cholesterol from the liver into bile. However, YM17E caused secre tory diarrhea in beagle dogs at near lipid lowering doses. When YM17E was administered at the same total dosage but divided into 5 daily administrations, the incidence of diarrhea was significantly reduced while its cholesterol lowering effect became stronger. These results suggest that the inhibition of intestinal and/or liver ACAT increases the risk of diarrhea development which, however, can be avoided by controlled drug administration in beagle dogs.

NTE-122, an Acyl-CoA:Cholesterol Acyltransferase Inhibitor, Prevents the Progression of Atherogenesis in Cholesterol-Fed Rabbits

“…During the experiments, body weight and food consumption (100 g /day) were not different among all groups, and rabbits given NTE-122 did not shown diarrhea (data not shown), although it was recently reported that an ACAT inhibitor caused diarrhea (11). The changes in plasma total cholesterol levels and liver total cholesterol content are shown in Fig.…”

Pyripyropene A, an Acyl–Coenzyme A:Cholesterol Acyltransferase 2–Selective Inhibitor, Attenuates Hypercholesterolemia and Atherosclerosis in Murine Models of Hyperlipidemia

“…Most ACAT inhibitors so far developed have had problems with side effects, such as diarrhea and toxicity to certain tissues. 39,40 Additionally, all the previously developed drugs except PPPA also inhibited ACAT1 activity, which may increase free cholesterol levels in macrophages and, with limited efflux of free cholesterol, potentially induce cytotoxicity, 8,10,17 although such severe effects were not prominent in all mouse experiments. PPPA showed no effect on macrophages in aortae and ACAT1 activity in macrophages, 24 leading us to expect that PPPA would show no toxic effect on macrophages in human beings.…”

Effect of SMP-500, a Novel Acyl-CoA:Cholesterol Acyltransferase Inhibitor, on the Cholesterol Esterification and Its Hypocholesterolemic Properties

“…Several ACAT inhibitors have been synthesized, and their pharmacological activities have been evaluated in animals and humans. However, there are several issues, such as side effects [2][3][4] and insufficient effects in humans [5,6], that must be overcome in the development of ACAT inhibitors as therapeutic agents.…”