The Experts below are selected from a list of 12 Experts worldwide ranked by ideXlab platform
Haruo Ohnishi - One of the best experts on this subject based on the ideXlab platform.
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Effects of F-1394, an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on ACAT activity in HepG2 cells and on hepatic secretion of lipids in Triton WR-1339-induced hyperlipidemic rats: possible role of hepatic ACAT in very low density lipoprote
Japanese Journal of Pharmacology, 1998Co-Authors: Katsumi Aragane, Jun Kusunoki, Tetsuya Kitamine, Tetsuaki Yamaura, Haruo OhnishiAbstract:Abstract We examined the inhibitory potency of F-1394 ((lS,2S)-2-[3-(2,2-dimethylpropyl)-3-nonylureido]cyclohexane-1-yl 3-[(4R)-N(2,2,5,5-tetramethyl-l,3-dioxane-4-carbonyl)amino]propionate), an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on ACAT activity and its hypolipidemic effect. F-1394 inhibited whole-cell ACAT activity in HepG2 cells with an IC50 value of 42 nM. The potency of F-1394 was greater than that of the five other ACAT inhibitors tested (YM-17E, CI-976, 57-118, CL-277,082 and DL-Melinamide). In rats made hyperlipidemic by Triton WR-1339, F-1394 caused a reduction in the hepatic secretion rate of cholesterol. These data suggest that inhibition of hepatic ACAT activity helps to reduce very low density lipoprotein secretion from the liver into the circulation.
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effect of f 1394 a potent and selective inhibitor of acyl coa cholesterol acyltransferase acat on esterification of cholesterol and basolateral secretion of cholesteryl ester in caco 2 cells
Folia Pharmacologica Japonica, 1997Co-Authors: Jun Kusunoki, Katsumi Aragane, Tetsuya Kitamine, Tetsuaki Yamaura, Haruo OhnishiAbstract:The present study was conducted to investigate the inhibitory effect of F-1394, a potent and selective inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), on incorporation of 14C-oleic acid into cholesteryl ester in cultured Caco-2 cells, a human intestinal cell line, and compare its effect to those of other ACAT inhibitors and hypolipidemic agents. The cholesterol esterification in Caco-2 cells was strongly inhibited by F-1394 in a concentration-dependent manner with the estimated IC50 value of 71 nM. In contrast, the estimated IC50 values of the other ACAT inhibitors such as YM-17E, CI-976, CL-277,082 and DL-Melinamide are 121 nM, 702 nM, 21.5 microM and 20.9 microM, respectively. Simvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, also inhibited the ACAT activity in Caco-2 cells with an IC50 value of 22.5 microM, whereas pravastatin Na, probucol and clofibrate did not affect the activity. Furthermore, F-1394 at a concentration of 100 nM inhibited the basolateral secretion of cholesteryl ester by 90% from differentiated Caco-2 cells that were cultured on a membrane filter. These results demonstrate that F-1394 strongly inhibits human intestinal ACAT activity and basolateral secretion of cholesterol from Caco-2 cells. Therefore, F-1394 may have a therapeutic potential for dietary hyperlipidemic subjects.
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hypocholesterolemic action and prevention of cholesterol absorption via the gut by f 1394 a potent acyl coa cholesterol acyltransferase acat inhibitor in cholesterol diet fed rats
Japanese Journal of Pharmacology, 1995Co-Authors: Jun Kusunoki, Katsumi Aragane, Tetsuya Kitamine, Tetsuaki Yamaura, Sakiko Higashinakagawa, Noriko Kase, Haruo OhnishiAbstract:In the present study, we investigated the hypocholesterolemic effect of F-1394 ((ls, 2s)-2-[3-(2, 2-dimethylpropyl)-3-nonylureido]aminocyclohexane-1-yl 3-[N-(2, 2, 5, 5-tetramethyl-1, 3-dioxane-4-carbonyl)amino]propionate), a potent and selective inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), and the effect on cholesterol absorption via the gut in rats fed a 1 % cholesterol diet. Single administration of F-1394 to the cholesterol diet-fed rats at the doses of 3-30 mg/kg, p.o. decreased the serum cholesterol levels by 16 - 54% 3 hr after the administration. The ACAT activity in the small intestinal mucosa of the rats given orally F-1394 (30 mg/kg) was significantly inhibited 3 hr after the administration. The hypocholesterolemic action of F-1394 had a faster onset than that of DL-Melinamide or CL-277, 082. The study by the dual isotope ratio method showed that F-1394 (30 mg/kg, p.o.) significantly suppressed the dietary cholesterol absorption. Furthermore, in the determination of cholesterol absorption by using 14C-cholesterol as the oral tracer, the administration of F-1394 (30 mg/kg, p.o.) 1 or 2 hr before or immediately after the application of the oral tracer significantly prevented the appearance of the radioactivity in the circulation by around 90%. These results indicate that oral administration of F-1394 inhibits the ACAT activity in the small intestinal mucosa and subsequently contributes much to the prevention of cholesterol absorption via the gut, resulting in the decrease in serum cholesterol levels in the cholesterol diet-fed rats. Furthermore, the effect of F-1394 appears immediately after its administration in contrast to that of DL-Melinamide or CL-277, 082.
Jun Kusunoki - One of the best experts on this subject based on the ideXlab platform.
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Effects of F-1394, an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on ACAT activity in HepG2 cells and on hepatic secretion of lipids in Triton WR-1339-induced hyperlipidemic rats: possible role of hepatic ACAT in very low density lipoprote
Japanese Journal of Pharmacology, 1998Co-Authors: Katsumi Aragane, Jun Kusunoki, Tetsuya Kitamine, Tetsuaki Yamaura, Haruo OhnishiAbstract:Abstract We examined the inhibitory potency of F-1394 ((lS,2S)-2-[3-(2,2-dimethylpropyl)-3-nonylureido]cyclohexane-1-yl 3-[(4R)-N(2,2,5,5-tetramethyl-l,3-dioxane-4-carbonyl)amino]propionate), an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on ACAT activity and its hypolipidemic effect. F-1394 inhibited whole-cell ACAT activity in HepG2 cells with an IC50 value of 42 nM. The potency of F-1394 was greater than that of the five other ACAT inhibitors tested (YM-17E, CI-976, 57-118, CL-277,082 and DL-Melinamide). In rats made hyperlipidemic by Triton WR-1339, F-1394 caused a reduction in the hepatic secretion rate of cholesterol. These data suggest that inhibition of hepatic ACAT activity helps to reduce very low density lipoprotein secretion from the liver into the circulation.
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effect of f 1394 a potent and selective inhibitor of acyl coa cholesterol acyltransferase acat on esterification of cholesterol and basolateral secretion of cholesteryl ester in caco 2 cells
Folia Pharmacologica Japonica, 1997Co-Authors: Jun Kusunoki, Katsumi Aragane, Tetsuya Kitamine, Tetsuaki Yamaura, Haruo OhnishiAbstract:The present study was conducted to investigate the inhibitory effect of F-1394, a potent and selective inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), on incorporation of 14C-oleic acid into cholesteryl ester in cultured Caco-2 cells, a human intestinal cell line, and compare its effect to those of other ACAT inhibitors and hypolipidemic agents. The cholesterol esterification in Caco-2 cells was strongly inhibited by F-1394 in a concentration-dependent manner with the estimated IC50 value of 71 nM. In contrast, the estimated IC50 values of the other ACAT inhibitors such as YM-17E, CI-976, CL-277,082 and DL-Melinamide are 121 nM, 702 nM, 21.5 microM and 20.9 microM, respectively. Simvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, also inhibited the ACAT activity in Caco-2 cells with an IC50 value of 22.5 microM, whereas pravastatin Na, probucol and clofibrate did not affect the activity. Furthermore, F-1394 at a concentration of 100 nM inhibited the basolateral secretion of cholesteryl ester by 90% from differentiated Caco-2 cells that were cultured on a membrane filter. These results demonstrate that F-1394 strongly inhibits human intestinal ACAT activity and basolateral secretion of cholesterol from Caco-2 cells. Therefore, F-1394 may have a therapeutic potential for dietary hyperlipidemic subjects.
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hypocholesterolemic action and prevention of cholesterol absorption via the gut by f 1394 a potent acyl coa cholesterol acyltransferase acat inhibitor in cholesterol diet fed rats
Japanese Journal of Pharmacology, 1995Co-Authors: Jun Kusunoki, Katsumi Aragane, Tetsuya Kitamine, Tetsuaki Yamaura, Sakiko Higashinakagawa, Noriko Kase, Haruo OhnishiAbstract:In the present study, we investigated the hypocholesterolemic effect of F-1394 ((ls, 2s)-2-[3-(2, 2-dimethylpropyl)-3-nonylureido]aminocyclohexane-1-yl 3-[N-(2, 2, 5, 5-tetramethyl-1, 3-dioxane-4-carbonyl)amino]propionate), a potent and selective inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), and the effect on cholesterol absorption via the gut in rats fed a 1 % cholesterol diet. Single administration of F-1394 to the cholesterol diet-fed rats at the doses of 3-30 mg/kg, p.o. decreased the serum cholesterol levels by 16 - 54% 3 hr after the administration. The ACAT activity in the small intestinal mucosa of the rats given orally F-1394 (30 mg/kg) was significantly inhibited 3 hr after the administration. The hypocholesterolemic action of F-1394 had a faster onset than that of DL-Melinamide or CL-277, 082. The study by the dual isotope ratio method showed that F-1394 (30 mg/kg, p.o.) significantly suppressed the dietary cholesterol absorption. Furthermore, in the determination of cholesterol absorption by using 14C-cholesterol as the oral tracer, the administration of F-1394 (30 mg/kg, p.o.) 1 or 2 hr before or immediately after the application of the oral tracer significantly prevented the appearance of the radioactivity in the circulation by around 90%. These results indicate that oral administration of F-1394 inhibits the ACAT activity in the small intestinal mucosa and subsequently contributes much to the prevention of cholesterol absorption via the gut, resulting in the decrease in serum cholesterol levels in the cholesterol diet-fed rats. Furthermore, the effect of F-1394 appears immediately after its administration in contrast to that of DL-Melinamide or CL-277, 082.
Katsumi Aragane - One of the best experts on this subject based on the ideXlab platform.
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Effects of F-1394, an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on ACAT activity in HepG2 cells and on hepatic secretion of lipids in Triton WR-1339-induced hyperlipidemic rats: possible role of hepatic ACAT in very low density lipoprote
Japanese Journal of Pharmacology, 1998Co-Authors: Katsumi Aragane, Jun Kusunoki, Tetsuya Kitamine, Tetsuaki Yamaura, Haruo OhnishiAbstract:Abstract We examined the inhibitory potency of F-1394 ((lS,2S)-2-[3-(2,2-dimethylpropyl)-3-nonylureido]cyclohexane-1-yl 3-[(4R)-N(2,2,5,5-tetramethyl-l,3-dioxane-4-carbonyl)amino]propionate), an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on ACAT activity and its hypolipidemic effect. F-1394 inhibited whole-cell ACAT activity in HepG2 cells with an IC50 value of 42 nM. The potency of F-1394 was greater than that of the five other ACAT inhibitors tested (YM-17E, CI-976, 57-118, CL-277,082 and DL-Melinamide). In rats made hyperlipidemic by Triton WR-1339, F-1394 caused a reduction in the hepatic secretion rate of cholesterol. These data suggest that inhibition of hepatic ACAT activity helps to reduce very low density lipoprotein secretion from the liver into the circulation.
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effect of f 1394 a potent and selective inhibitor of acyl coa cholesterol acyltransferase acat on esterification of cholesterol and basolateral secretion of cholesteryl ester in caco 2 cells
Folia Pharmacologica Japonica, 1997Co-Authors: Jun Kusunoki, Katsumi Aragane, Tetsuya Kitamine, Tetsuaki Yamaura, Haruo OhnishiAbstract:The present study was conducted to investigate the inhibitory effect of F-1394, a potent and selective inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), on incorporation of 14C-oleic acid into cholesteryl ester in cultured Caco-2 cells, a human intestinal cell line, and compare its effect to those of other ACAT inhibitors and hypolipidemic agents. The cholesterol esterification in Caco-2 cells was strongly inhibited by F-1394 in a concentration-dependent manner with the estimated IC50 value of 71 nM. In contrast, the estimated IC50 values of the other ACAT inhibitors such as YM-17E, CI-976, CL-277,082 and DL-Melinamide are 121 nM, 702 nM, 21.5 microM and 20.9 microM, respectively. Simvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, also inhibited the ACAT activity in Caco-2 cells with an IC50 value of 22.5 microM, whereas pravastatin Na, probucol and clofibrate did not affect the activity. Furthermore, F-1394 at a concentration of 100 nM inhibited the basolateral secretion of cholesteryl ester by 90% from differentiated Caco-2 cells that were cultured on a membrane filter. These results demonstrate that F-1394 strongly inhibits human intestinal ACAT activity and basolateral secretion of cholesterol from Caco-2 cells. Therefore, F-1394 may have a therapeutic potential for dietary hyperlipidemic subjects.
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hypocholesterolemic action and prevention of cholesterol absorption via the gut by f 1394 a potent acyl coa cholesterol acyltransferase acat inhibitor in cholesterol diet fed rats
Japanese Journal of Pharmacology, 1995Co-Authors: Jun Kusunoki, Katsumi Aragane, Tetsuya Kitamine, Tetsuaki Yamaura, Sakiko Higashinakagawa, Noriko Kase, Haruo OhnishiAbstract:In the present study, we investigated the hypocholesterolemic effect of F-1394 ((ls, 2s)-2-[3-(2, 2-dimethylpropyl)-3-nonylureido]aminocyclohexane-1-yl 3-[N-(2, 2, 5, 5-tetramethyl-1, 3-dioxane-4-carbonyl)amino]propionate), a potent and selective inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), and the effect on cholesterol absorption via the gut in rats fed a 1 % cholesterol diet. Single administration of F-1394 to the cholesterol diet-fed rats at the doses of 3-30 mg/kg, p.o. decreased the serum cholesterol levels by 16 - 54% 3 hr after the administration. The ACAT activity in the small intestinal mucosa of the rats given orally F-1394 (30 mg/kg) was significantly inhibited 3 hr after the administration. The hypocholesterolemic action of F-1394 had a faster onset than that of DL-Melinamide or CL-277, 082. The study by the dual isotope ratio method showed that F-1394 (30 mg/kg, p.o.) significantly suppressed the dietary cholesterol absorption. Furthermore, in the determination of cholesterol absorption by using 14C-cholesterol as the oral tracer, the administration of F-1394 (30 mg/kg, p.o.) 1 or 2 hr before or immediately after the application of the oral tracer significantly prevented the appearance of the radioactivity in the circulation by around 90%. These results indicate that oral administration of F-1394 inhibits the ACAT activity in the small intestinal mucosa and subsequently contributes much to the prevention of cholesterol absorption via the gut, resulting in the decrease in serum cholesterol levels in the cholesterol diet-fed rats. Furthermore, the effect of F-1394 appears immediately after its administration in contrast to that of DL-Melinamide or CL-277, 082.
Toshio Kamei - One of the best experts on this subject based on the ideXlab platform.
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n 2 n pentyl 6 6 dimethyl 2 4 heptadiynyl amino ethyl 2 methyl 1 naphthylthio acetamide fy 087 a new acyl coenzyme a cholesterol acyltransferase acat inhibitor of diet induced atherosclerosis formation in mice
Biochemical Pharmacology, 1995Co-Authors: Yasufumi Nagata, Mari Yonemoto, Yoshikazu Iwasawa, Akiko Shimizunagumo, Hiromi Hattori, Yoshio Sawazaki, Toshio KameiAbstract:Abstract FY-087 ( N -[2-[ N ′-pentyl-(6,6-dimethyl-2,4-heptadiynyl)amino]ethyl]-(2-methyl-1-naphthyl-thio)acetamide) was found to be a competitive inhibitor of human microsomal acyl coenzyme A:cholesterol acyltransferase (ACAT) with an ic 50 value of 0.11 μM. Under our assay conditions, other ACAT inhibitors tested, specifically YM-750, E-5324, and Melinamide, all of which are now in phase I clinical trials or in clinical use in Japan, inhibited this enzyme with ic 50 values of 0.18, 0.14, and 3.2 μM, respectively. FY-087 also inhibited ACAT in acetyl-low density lipoprotein loaded human macrophages (THP-1 cells) with an ic 50 of 0.17 μM. Following the oral administration of FY-087 (30 mg/ kg) to rats, the plasma concentration of FY-087 reached 0.42 μg/mL after 2 hr. This concentration of FY-087 was enough to inhibit blood vessel ACAT activity. Cholesterol-lowering and anti-atherogenic effects of FY-087 were examined using C57BL/6J mice fed an atherogenic diet. In this mouse model, treatment with FY-087 (28 mg/kg) inhibited the increase in plasma cholesterol levels by about 20% and decreased the hepatic accumulation of free and esterified cholesterol by 61 and 67%, respectively. FY-087 also significantly inhibited the atherogenic diet-induced increase in the fatty-streak lesion area of the proximal aorta by 57% in C57BL/6J mice. These results indicate that FY-087 is not only a therapeutically bioavailable ACAT inhibitor that lowers plasma cholesterol levels, but also an effective anti-atherogenic agent in mice fed an atherogenic diet.
Tetsuya Kitamine - One of the best experts on this subject based on the ideXlab platform.
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Effects of F-1394, an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on ACAT activity in HepG2 cells and on hepatic secretion of lipids in Triton WR-1339-induced hyperlipidemic rats: possible role of hepatic ACAT in very low density lipoprote
Japanese Journal of Pharmacology, 1998Co-Authors: Katsumi Aragane, Jun Kusunoki, Tetsuya Kitamine, Tetsuaki Yamaura, Haruo OhnishiAbstract:Abstract We examined the inhibitory potency of F-1394 ((lS,2S)-2-[3-(2,2-dimethylpropyl)-3-nonylureido]cyclohexane-1-yl 3-[(4R)-N(2,2,5,5-tetramethyl-l,3-dioxane-4-carbonyl)amino]propionate), an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on ACAT activity and its hypolipidemic effect. F-1394 inhibited whole-cell ACAT activity in HepG2 cells with an IC50 value of 42 nM. The potency of F-1394 was greater than that of the five other ACAT inhibitors tested (YM-17E, CI-976, 57-118, CL-277,082 and DL-Melinamide). In rats made hyperlipidemic by Triton WR-1339, F-1394 caused a reduction in the hepatic secretion rate of cholesterol. These data suggest that inhibition of hepatic ACAT activity helps to reduce very low density lipoprotein secretion from the liver into the circulation.
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effect of f 1394 a potent and selective inhibitor of acyl coa cholesterol acyltransferase acat on esterification of cholesterol and basolateral secretion of cholesteryl ester in caco 2 cells
Folia Pharmacologica Japonica, 1997Co-Authors: Jun Kusunoki, Katsumi Aragane, Tetsuya Kitamine, Tetsuaki Yamaura, Haruo OhnishiAbstract:The present study was conducted to investigate the inhibitory effect of F-1394, a potent and selective inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), on incorporation of 14C-oleic acid into cholesteryl ester in cultured Caco-2 cells, a human intestinal cell line, and compare its effect to those of other ACAT inhibitors and hypolipidemic agents. The cholesterol esterification in Caco-2 cells was strongly inhibited by F-1394 in a concentration-dependent manner with the estimated IC50 value of 71 nM. In contrast, the estimated IC50 values of the other ACAT inhibitors such as YM-17E, CI-976, CL-277,082 and DL-Melinamide are 121 nM, 702 nM, 21.5 microM and 20.9 microM, respectively. Simvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, also inhibited the ACAT activity in Caco-2 cells with an IC50 value of 22.5 microM, whereas pravastatin Na, probucol and clofibrate did not affect the activity. Furthermore, F-1394 at a concentration of 100 nM inhibited the basolateral secretion of cholesteryl ester by 90% from differentiated Caco-2 cells that were cultured on a membrane filter. These results demonstrate that F-1394 strongly inhibits human intestinal ACAT activity and basolateral secretion of cholesterol from Caco-2 cells. Therefore, F-1394 may have a therapeutic potential for dietary hyperlipidemic subjects.
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hypocholesterolemic action and prevention of cholesterol absorption via the gut by f 1394 a potent acyl coa cholesterol acyltransferase acat inhibitor in cholesterol diet fed rats
Japanese Journal of Pharmacology, 1995Co-Authors: Jun Kusunoki, Katsumi Aragane, Tetsuya Kitamine, Tetsuaki Yamaura, Sakiko Higashinakagawa, Noriko Kase, Haruo OhnishiAbstract:In the present study, we investigated the hypocholesterolemic effect of F-1394 ((ls, 2s)-2-[3-(2, 2-dimethylpropyl)-3-nonylureido]aminocyclohexane-1-yl 3-[N-(2, 2, 5, 5-tetramethyl-1, 3-dioxane-4-carbonyl)amino]propionate), a potent and selective inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), and the effect on cholesterol absorption via the gut in rats fed a 1 % cholesterol diet. Single administration of F-1394 to the cholesterol diet-fed rats at the doses of 3-30 mg/kg, p.o. decreased the serum cholesterol levels by 16 - 54% 3 hr after the administration. The ACAT activity in the small intestinal mucosa of the rats given orally F-1394 (30 mg/kg) was significantly inhibited 3 hr after the administration. The hypocholesterolemic action of F-1394 had a faster onset than that of DL-Melinamide or CL-277, 082. The study by the dual isotope ratio method showed that F-1394 (30 mg/kg, p.o.) significantly suppressed the dietary cholesterol absorption. Furthermore, in the determination of cholesterol absorption by using 14C-cholesterol as the oral tracer, the administration of F-1394 (30 mg/kg, p.o.) 1 or 2 hr before or immediately after the application of the oral tracer significantly prevented the appearance of the radioactivity in the circulation by around 90%. These results indicate that oral administration of F-1394 inhibits the ACAT activity in the small intestinal mucosa and subsequently contributes much to the prevention of cholesterol absorption via the gut, resulting in the decrease in serum cholesterol levels in the cholesterol diet-fed rats. Furthermore, the effect of F-1394 appears immediately after its administration in contrast to that of DL-Melinamide or CL-277, 082.