@article{3062494, title = "EP2306 [2-(4-biphenyl)-4-methyl-octahydro-1,4-benzoxazin-2-ol, hydrobromide], a novel squalene synthase inhibitor, reduces atherosclerosis in the cholesterol-fed rabbit", author = "Tavridou, A. and Kaklamanis, L. and Papalois, A. and Kourounakis, A.P. and Rekka, E.A. and Kourounakis, P.N. and Charalambous, A. and Manolopoulos, V.G.", journal = "JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS", year = "2007", volume = "323", number = "3", pages = "794-804", issn = "0022-3565", doi = "10.1124/jpet.107.126375", keywords = "2 (4 biphenyl) 4 methyl octahydro 1,4 benzoxazin 2 ol; 2 [1 [2 [1 (3 acetoxy 2,2 dimethylpropyl) 7 chloro 5 (2,3 dimethoxyphenyl) 2 oxo 1,2,3,5 tetrahydrobenzo[e][1,4]oxazepin 3 yl]acetyl]piperidin 4 yl]acetic acid; 2 [2 fluoro 2 (quinuclidin 3 ylidene)ethoxy] 9h carbazole; 5 [n [2 butenyl 3 (2 methoxyphenyl)] n methylamino] 1,1 pentylidenebis(phosphonic acid)tripivaloyloxymethyl ester; aminotransferase; cholesterol; ep 2306; er 27856; ezetimibe; high density lipoprotein cholesterol; low density lipoprotein cholesterol; simvastatin; squalene synthase; squalene synthase inhibitor; tak 475; triacylglycerol; unclassified drug; ym 53601, animal experiment; animal model; animal tissue; antioxidant activity; article; atherosclerosis; cholesterol blood level; cholesterol diet; combination chemotherapy; controlled study; coronary artery disease; enzyme inhibition; lipogenesis; male; monotherapy; nonhuman; priority journal; rabbit; triacylglycerol blood level, Animals; Atherosclerosis; Biphenyl Compounds; Cholesterol, Dietary; Diet, Atherogenic; Enzyme Inhibitors; Farnesyl-Diphosphate Farnesyltransferase; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipid Metabolism; Lipids; Liver; Male; Morpholines; Organ Specificity; Rabbits", abstract = "EP2306 [2-(4-biphenyl)-4-methyl-octahydro-1,4-benzoxazin-2-ol, hydrobromide] inhibits squalene synthase and lipid biosynthesis and possesses antioxidant properties. We hypothesized that EP2306 can effectively modify circulating lipids and reduce atherosclerosis in the cholesterol-fed rabbit. Animals were fed a high-cholesterol diet for 4 weeks followed by 4 (phase 1 and 2) or 12 weeks (phase 3) of drug treatment while on high-cholesterol diet. In phase 1, the dose-effect relationship of EP2306 on lipids and atherosclerosis was established, and its most effective dose was determined (2 mg/kg). This dose reduced significantly total cholesterol (512 ± 96 mg/dl before versus 320 ± 124 mg/dl after treatment, p < 0.05) and atherosclerotic lesions compared with control animals. In phase 2, the effects of 2 mg/kg EP2306, 2.5 mg/kg simvastatin, and their combination were assessed. Although no significant effect on lipid parameters was observed, there was a significant reduction (35 ± 5%, p < 0.05) of atherosclerotic lesions in animals treated with EP2306, a similar reduction with simvastatin, and a further reduction (48 ± 7%, p < 0.05) when the two agents were combined. In animals treated for 12 weeks with the drugs (phase 3), only EP2306 significantly reduced atherosclerotic lesions by more than 50%, whereas simvastatin alone or in combination with EP2306 had no effect. Treatment with EP2306 did not adversely affect liver transaminases or cause any histopathological changes on various organs of the animals. In conclusion, we have shown that EP2306 inhibits atherosclerosis in vivo, indicating potential as a novel therapeutic agent for coronary artery disease and other atherosclerosis-related disorders. Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics." }