The cholesterol-lowering and anti-atherosclerotic effects of NTE-122 (trans-1,4-bis[[1-cyclohexyl-3-(4-dimethylaminophenyl)ureido]methyl]cyclohexane), an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, were evaluated in 1% cholesterol diet-fed rabbits. NTE-122 (1, 3 and 10 mg/kg per day) lowered the total cholesterol levels in both plasma and liver dose-dependently (by 99% and 94% at 10 mg/kg per day, respectively). In the aortic wall of the rabbits given NTE-122, the atherosclerotic lesion area in both aortic arch and thoracic aorta were dose-dependently reduced (by 100% at 10 mg/kg per day), and the total cholesterol content in aortic arch was also lowered significantly at more than 3 mg/kg per day. These results suggest that NTE-122 is capable of exhibiting anti-atherosclerotic effects.

01 Jan 1999·Folia Pharmacologica Japonica

Glbbenclamide inhibits cholesterol metabolism in macrophage

Article

Author: Ohgami, N ; Nakayama, H ; Kuniyasu, A ; Horiuchi, S ; Miyazaki, A ; Hakamata, H

Sulfonylureas are generally used in the therapeutic treatment of non-insulin-dependent diabetes mellitus. Little is known, however, whether they also affect the lipid metabolism. Using glibenclamide (GB), a typical sulfonylurea, we have investigated its effects on the lipid metabolism in macrophages, J774 and phorbol ester-treated THP-1 cells. In the whole-cell assay system for cholesteryl ester (CE) accumulation that is induced by addition of chemically modified low-density lipoprotein (LDL), such as Ac-LDL and ox-LDL, GB effectively inhibited the CE accumulation of J774 cells in dose-dependent manners. The inhibition was resulted from increase in free cholesterol but not from change in total cholesterol amount. The results suggest that GB acts on acyl-CoA: cholesterol acyltransferase (ACAT) and inhibits its activity. To confirm the possibility, we then tested GB by another assay system using ACAT that was solubilized from the cells and reconstituted into the liposome composed of phosphatidyl choline- cholesterol. GB inhibition was not so much effective as those by CI-976 and NTE-122, known ACAT inhibitors, but the inhibition was complete in the presence of 100 microM GB. Using cell homogenates of PMA-stimulated THP-1 cells, GB also inhibited the ACAT activity to the level of undifferentiated THP-1 cells. These results indicate that GB acts as ACAT inhibitor but the chemical structure is quite different from the conventional ACAT inhibitors, suggesting it can be a seed to generate potential ACAT inhibitors which do not exhibit toxicity in adrenal gland.

01 Jan 1999·Japanese Journal of Pharmacology

Effects of NTE-122, a Novel Acyl-CoA:Cholesterol Acyltransferase Inhibitor, on Cholesterol Esterification and High-Density Lipoprotein-Induced Cholesterol Efflux in Macrophages

Article

Author: Yoichi Nobuhara ; Toshihiro Yamada ; Yukimasa Azuma ; Katsutoshi Ohno ; Takashi Kawasaki ; Masahiro Yamasaki ; Kiyohito Ikemoto

We investigated the effects of a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, NTE-122 (trans-1,4-bis[[1-cyclohexyl-3-(4-dimethylamino phenyl)ureido]methyl]cyclohexane), on ACAT activities in macrophages originating from several species and high-density lipoprotein (HDL)-induced cholesterol efflux in phorbol 12-myristate 13-acetate (PMA)-treated THP-1 cells. NTE-122 inhibited cell-free ACAT activities in human PMA-treated THP-1 cells and mouse J774.1 cells with IC50 values of 0.88 and 360 nM, respectively. NTE-122 competively inhibited the ACAT activity in PMA-treated THP-1 cells. NTE-122 also inhibited cellular ACAT activities in PMA-treated THP-1 cells, rat peritoneal macrophages and J774.1 cells with IC50 values of 3.5, 84 and 6800 nM, respectively. Furthermore, NTE-122 prevented cholesterol accumulation in PMA-treated THP-1 cells incubated with acetylated low density lipoprotein, simultaneously with HDL, while it caused accumulation of a significant amount of free cholesterol in the absence and even in the presence of HDL. NTE-122 also enhanced HDL-induced cholesterol efflux from established foam cells converted from PMA-treated THP-1 cells. These results suggest that NTE-122, capable of inhibiting macrophage ACAT activity in humans more strongly than those in the other species, exhibits anti-atherogenic effects by preventing the foam cell formation and enhancing the foam cell regression in humans.

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Indication	Highest Phase	Country/Location	Organization	Date
Arteriosclerosis	Preclinical	JP	Nissin Food Products Co., Ltd.	-
Hyperlipidemias	Preclinical	JP	Nissin Food Products Co., Ltd.	-

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