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Effect of E5324, a novel inhibitor of acyl-CoA:cholesterol acyltransferase, on cholesteryl ester synthesis and accumulation in macrophages. 1995

M Kogushi, and H Tanaka, and H Kobayashi, and T Yamada, and I Ohtsuka, and T Kimura, and I Saito
Eisai Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.

The in vitro potencies of a novel inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), E5324 (n-butyl-N'-[2-[3-(5-ethyl-4-phenyl-1H-imidazol-1-yl)propoxy]-6- methylphenyl]urea), were studied. E5324 was found to be a potent ACAT inhibitor in microsomes from a various tissues and in cultured cell homogenate, with IC50 values in the range of 0.044 to 0.19 microM. The kinetic study on E5324 showed that the inhibition of rat intestine ACAT was competitive with respect to oleoyl CoA. E5324 inhibited [3H]olate incorporation into cholesteryl [3H]oleate in phorbol ester-treated THP-1 cell lines (IC50 = 0.44 microM). The rate of [3H]oleate incorporation into phospholipids and triglycerides was not affected by E5324. In an experiment with [3H]cholesterol as the substrate for ACAT, E5324 also inhibited [3H]cholesteryl ester synthesis (IC50 = 0.41 microM). Furthermore, E5324 prevented accumulation of both esterified and total cholesterol in acetyl low density lipoprotein-loaded THP-1 cells. These results indicate that E5324 is a potent and selective ACAT inhibitor and prevents cholesteryl ester accumulation in macrophages.

UI MeSH Term Description Entries
D008074 Lipoproteins Lipid-protein complexes involved in the transportation and metabolism of lipids in the body. They are spherical particles consisting of a hydrophobic core of TRIGLYCERIDES and CHOLESTEROL ESTERS surrounded by a layer of hydrophilic free CHOLESTEROL; PHOSPHOLIPIDS; and APOLIPOPROTEINS. Lipoproteins are classified by their varying buoyant density and sizes. Circulating Lipoproteins,Lipoprotein,Lipoproteins, Circulating
D008264 Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood MONOCYTES. Main types are PERITONEAL MACROPHAGES; ALVEOLAR MACROPHAGES; HISTIOCYTES; KUPFFER CELLS of the liver; and OSTEOCLASTS. They may further differentiate within chronic inflammatory lesions to EPITHELIOID CELLS or may fuse to form FOREIGN BODY GIANT CELLS or LANGHANS GIANT CELLS. (from The Dictionary of Cell Biology, Lackie and Dow, 3rd ed.) Bone Marrow-Derived Macrophages,Monocyte-Derived Macrophages,Macrophage,Macrophages, Monocyte-Derived,Bone Marrow Derived Macrophages,Bone Marrow-Derived Macrophage,Macrophage, Bone Marrow-Derived,Macrophage, Monocyte-Derived,Macrophages, Bone Marrow-Derived,Macrophages, Monocyte Derived,Monocyte Derived Macrophages,Monocyte-Derived Macrophage
D008297 Male Males
D009829 Oleic Acids A group of fatty acids that contain 18 carbon atoms and a double bond at the omega 9 carbon. Octadecenoic Acids,Acids, Octadecenoic,Acids, Oleic
D010671 Phenylurea Compounds Compounds that include the amino-N-phenylamide structure. Phenylcarbamides,Phenylurea Derivatives,Compounds, Phenylurea,Derivatives, Phenylurea
D011817 Rabbits A burrowing plant-eating mammal with hind limbs that are longer than its fore limbs. It belongs to the family Leporidae of the order Lagomorpha, and in contrast to hares, possesses 22 instead of 24 pairs of chromosomes. Belgian Hare,New Zealand Rabbit,New Zealand Rabbits,New Zealand White Rabbit,Rabbit,Rabbit, Domestic,Chinchilla Rabbits,NZW Rabbits,New Zealand White Rabbits,Oryctolagus cuniculus,Chinchilla Rabbit,Domestic Rabbit,Domestic Rabbits,Hare, Belgian,NZW Rabbit,Rabbit, Chinchilla,Rabbit, NZW,Rabbit, New Zealand,Rabbits, Chinchilla,Rabbits, Domestic,Rabbits, NZW,Rabbits, New Zealand,Zealand Rabbit, New,Zealand Rabbits, New,cuniculus, Oryctolagus
D002784 Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Epicholesterol
D002785 Sterol O-Acyltransferase An enzyme that catalyzes the formation of cholesterol esters by the direct transfer of the fatty acid group from a fatty acyl CoA derivative. This enzyme has been found in the adrenal gland, gonads, liver, intestinal mucosa, and aorta of many mammalian species. EC 2.3.1.26. Acyl-CoA-Cholesterol Acyltransferase,Cholesterol Acyltransferase,Cholesterol Esterifying Enzyme,Acyl CoA Cholesterol Acyltransferase,Acyltransferase, Acyl-CoA-Cholesterol,Acyltransferase, Cholesterol,Enzyme, Cholesterol Esterifying,Esterifying Enzyme, Cholesterol,O-Acyltransferase, Sterol,Sterol O Acyltransferase
D002788 Cholesterol Esters Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. Cholesterol Ester,Cholesteryl Ester,Cholesteryl Esters,Ester, Cholesterol,Ester, Cholesteryl,Esters, Cholesterol,Esters, Cholesteryl
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme

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