Yuri Sakuma, Hiroyuki Hagihara, Kazuhiko Ohne, Akira Nagayoshi, Seitaro Mutoh (*), Yoshikuni Ito, Yoshitada Notsu and Masakuni Okuhara
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 5-2-3, Tokodai, Tsukuba, Ibaraki 300-26, Japan (*) To whom correspondence should be addressed.
Abstract: FR129169 (FR) (N-(1,2-diphenylethyl)-2-octyloxyphenylacetamide) has been found to inhibit acyl-CoA:cholesterol acyltransferase (ACAT) activities in intestinal microsomes of rats and rabbits and the liver homogenate of rats with IC50 values of around 1.0 x 10-7 M. The inhibitory activity was 2-3 times more potent than that of CI 976 (CI). When FR in a dose of 10 mg/kg/day was administered as a dietary admixture, plasma cholesterol levels were normalized in rats fed a high cholesterol diet, but lower doses of FR had no effect. Similar results were obtained in the rats treated with CI. The ex vivo study where hepatic ACAT activity was measured after oral dosing of the two inhibitors revealed that ACAT activity was significantly reduced in rats treated with FR in a dose of 10 mg/kg/day, while CI reduced the activity at lower doses such as 0.1 and 1 mg/kg/day. Since FR was not orally absorbed, it is speculated that the inhibitory activity of FR on hepatic ACAT in the ex vivo study results from the reduction of plasma cholesterol levels. These results suggest that FR exerted cholesterol-lowering activity mainly through inhibition of intestinal ACAT activity. The significance of intestinal ACAT inhibition by FR for therapeutic treatment of hypercholesterolemia is discussed.
Keywords:
Acyl-CoA:cholesterol acyltransferase, Atherosclerosis,
Hypercholesterolemia, Cholesterol absorption, FR129169