benzofurans and Arteriosclerosis

BO-653 is an antioxidant under development by Chugai for the potential treatment of atherosclerosis and the prevention of restenosis. By November 2001, BO-653 was in phase II trials for restenosis in post-percutaneous transluminal coronary angioplasty in the US, and by April 2002, the compound was in phase I trials for the same indication in Japan.

Topics: Animals; Antioxidants; Arteriosclerosis; Benzofurans; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Coronary Restenosis; Humans

Topics: Anilides; Animals; Arteriosclerosis; Benzofurans; Cholesterol Esters; Cyclohexanes; Dioxanes; Endothelium, Vascular; Humans; Hyperlipidemias; Imidazoles; Intestine, Small; Liver; Organ Specificity; Phenylurea Compounds; Sterol O-Acyltransferase; Urea

With increasing evidence that shows the involvement of active oxygen and nitrogen species in a variety of disorders, cancer, and aging, the role of antioxidant against oxidative stress has received renewed attention. In this review article, a rationale for design of lipophilic, radical-scavenging antioxidant is presented and the potency of a novel antioxidant, 2,3-dihydro-5-hydroxy-2,2-dipentyl-4, 6-di-tert-butylbenzofuran (BO-653), as an inhibitor of LDL oxidation was evaluated by considering various factors such as reactivity toward radicals, localization, and mobility in the lipoprotein, and fate of its radical. The anti-atherogenic activity of BO-653 was compared with those of alpha-tocopherol, probucol, and its metabolites. Furthermore, a novel function of phenolic antioxidants such as cell regulation and induction of phase II defense antioxidants are also discussed.

Topics: Animals; Antioxidants; Arteriosclerosis; Benzofurans; Drug Design; Drug Stability; Free Radical Scavengers; Humans; Vitamin E

Topics: Acute Disease; Arteriosclerosis; Benzofurans; Cholesterol; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Myocardial Infarction; Transaminases; Uric Acid; Vasodilator Agents

BO-653, 2,3-dihydro-5-hydroxy-4,6-di-tert-butyl-2,2-dipentylbenzofuran, is a synthetic antioxidant which is now being developed as an anti-atherogenic drug. The antioxidant action of BO-653 against lipid peroxidation in rat plasma was studied and compared with its analogue BO-653M, 2,3-dihydro-5-hydroxy-4,6-di-methyl-2,2-dipentylbenzofuran, and vitamin E. BO-653 was readily incorporated into plasma by oral administration and it inhibited plasma lipid peroxidation more efficiently than vitamin E independent of the presence or absence of vitamin C. On the other hand, its analogue BO-653M having two methyl substituents in place of tert-butyl groups of BO-653 did not inhibit the lipid peroxidation in plasma as efficiently as BO-653, demonstrating clearly that the tert-butyl groups at the ortho-position play a key role in determining the antioxidant efficacy.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Benzofurans; Lipid Peroxidation; Male; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Vitamin E

Antioxidants have been considered as potential antiatherogenic agents by inhibiting oxidation of low-density lipoprotein (LDL), albeit vitamin E, a natural antioxidant, has failed to show reduction on atherosclerosis in clinical trials. We have rationally designed and synthesized a novel series of antioxidants, 4,6-di-tert-butyl-2,3-dihydro-5-benzofuranols, to overcome the clinical limitation of vitamin E. In vitro, the compounds showed a potent inhibitory effect on lipid peroxidation detected as 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo[1,2-a]pyrazin-3-one (MCLA)-dependent chemiluminescence in linoleic acid autoxidation. They also inhibited the LDL oxidation induced by Cu(2+), and the inhibition is more potent than that of vitamin E and probucol. In vivo, 4,6-di-tert-butyl-2,3-dihydro-2,2-dipentyl-5-benzofuranol (BO-653, 1f), an optimal compound, showed the highest concentration in plasma and LDL fraction in Watanabe heritable hyperlipidemic rabbits, due to its high affinity to LDL. The isolated LDL samples from the 1f-treated rabbits showed potent resistibility to LDL oxidation. Compound 1f has been taken into clinical trials.

Topics: alpha-Tocopherol; Animals; Antioxidants; Arteriosclerosis; Benzofurans; Free Radicals; Linoleic Acid; Lipoproteins, LDL; Luminescent Measurements; Oxidation-Reduction; Rabbits; Structure-Activity Relationship

Antioxidants have been proposed as a promising treatment for restenosis after percutaneous transluminal coronary angioplasty (PTCA), but their mechanism of action remains unclear. Here, we investigated the effect of antioxidants on gene expression in the artery after balloon denudation. We developed a sensitive ribonuclease (RNase) protection assay for the messenger RNA (mRNA) levels of immediate early (IE) genes (c-jun, c-fos and c-myc), as well as platelet-derived growth factor-A (PDGF-A), platelet-derived growth factor-beta receptor, transforming growth factor-beta 1, and vascular endothelial growth factor. New Zealand White rabbits were fed a 0.17% cholesterol diet containing vehicle, BO-653 or probucol, and balloon denudation for iliac arteries was performed. The iliac arteries were then removed at 4 h after the denudation, for IE genes, and 10 days after for growth factors and receptors. Both BO-653 and probucol significantly reduced neointimal thickening, compared with the control. In terms of gene expression, BO-653, but not probucol, significantly inhibited c-myc induction. On the other hand, probucol, but not BO-653, significantly inhibited PDGF-A expression. Neither treatment had any effect on the expression of other genes. These results suggest that antioxidants affect the gene expression of the neointimal response and that both BO-653 and probucol inhibit gene expression in specific manners.

Topics: Analysis of Variance; Animals; Antioxidants; Arteriosclerosis; Base Sequence; Benzofurans; Catheterization; Cholesterol, Dietary; Diet, Atherogenic; Disease Models, Animal; Gene Expression; Genes, myc; Iliac Artery; Male; Molecular Sequence Data; Platelet-Derived Growth Factor; Probability; Probucol; Rabbits; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The effects of SR-A I/II deficiency and a synthetic anti-oxidant BO-653 on a diet-induced atherosclerosis in C57BL/6J, an inbred strain known to be susceptible to diet-induced atherosclerotic lesion formation, were examined. Quantitative analysis of the extent of atherosclerotic lesions in the mice fed the high-fat diet revealed that the atherosclerotic lesion area in SR-A I/II mutants was significantly reduced by 70% compared to wild type mice. A similar level of lesion reduction (75%) was found in wild type mice fed the high-fat diet supplemented with 0.6% BO-653 compared to those without BO-653. Thus, for C57BL/6J in the setting of prolonged exposure to a high-fat diet, defect of SR-A I/II expression is significantly protective against the development of atherosclerosis, as is the synthetic anti-oxidant BO-653. These results indicate that SR-A I/II has a crucial role in atherosclerotic lesion formation with uptake of oxidized-LDL in this mouse model.

Topics: Animals; Antioxidants; Arteriosclerosis; Benzofurans; CD36 Antigens; Cholesterol; Cholesterol, HDL; Diet; Female; Lipoproteins, LDL; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Mutation; Scavenger Receptors, Class A

2, 3-Dihydro-5-hydroxy-2, 2-dipentyl-4, 6-di-tert-butylbenzofuran (BO-653) and probucol, which act as radical scavenging antioxidants, were developed as anti-atherosclerotic medicines. In order to investigate the effect of these antioxidants on cell functions, we analyzed their ability to regulate gene expression in cultured human umbilical vein endothelial cells (HUVECs) using an oligonucleotide chip. Among 6,416 genes, 17 genes including those encoding mitochondrial proteins and proteins related to oxidative stress response were induced more than 3 fold by BO-653, probucol and tert-butylated hydroquinone (BHO). On the other hand, genes of three subunits of proteasome (PSMA2, PSMA3, PSMA4) were down-regulated by these antioxidants. A gene of cytochrome P-450 1A1 isozyme, a drug-metabolizing phase I enzyme, was expressed only by BHQ treatment. These results suggested that anti-atherogenic antioxidants affected gene expression in HUVECs by which they might regulate cell functions against oxidative stress.

Topics: Antioxidants; Arteriosclerosis; Benzofurans; Cells, Cultured; Cysteine Endopeptidases; Cytochrome P-450 CYP1A1; Endothelium, Vascular; Female; Gene Expression; Humans; Hydroquinones; Male; Multienzyme Complexes; Oligonucleotide Array Sequence Analysis; Oxidative Stress; Probucol; Proteasome Endopeptidase Complex; RNA, Messenger

Antioxidants have been proposed to have antiatherogenic potential by their inhibition of low density lipoprotein (LDL) oxidation. Here, we report an antioxidant, BO-653 (2,3-dihydro-5-hydroxy-2, 2-dipentyl-4,6-di-tert-butylbenzofuran), designed to exhibit antioxidative potency comparable to that of alpha-tocopherol, but yet possess a high degree of lipophilicity comparable to that of probucol. BO-653 exhibits a high affinity for LDL and is well distributed in aortic vessels in vivo. In atherosclerosis models of rabbits and mice, BO-653 has been shown to be able to suppress the formation of atherosclerotic lesions without untoward side effects. Specifically, there was no reduction of high density lipoprotein levels. This antioxidant provides additional evidence in support of the oxidized-LDL hypothesis, and itself is a promising candidate antioxidant for clinical use.

Topics: Animals; Antioxidants; Arteriosclerosis; Benzofurans; Dietary Fats; Disease Models, Animal; Drug Evaluation, Preclinical; Female; In Vitro Techniques; Lipoproteins, HDL; Lipoproteins, LDL; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Oxidation-Reduction; Rabbits; Receptors, LDL

2,3-Dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butyl-benzofuran (BO-653) is a novel antioxidant synthesized by theoretical designing based on the previous experimental findings and consideration. The antioxidant activities of BO-653 against the oxidative modification of low-density lipoprotein (LDL) induced by free radicals were studied. BO-653 was consumed faster than endogenous alpha-tocopherol and inhibited the formation of lipid hydroperoxides, which was observed during the consumption of alpha-tocopherol. Doxyl stearic acids incorporated into LDL as spin probes competed with the antioxidants in scavenging radicals. It was found that the efficacy of radical scavenging by alpha-tocopherol became smaller as the radical went deeper into the interior of LDL particle, whereas that by BO-653 did not change. Ascorbic acid in the aqueous phase spared alpha-tocopherol efficiently during oxidation. On the other hand, the sparing effect of ascorbic acid for BO-653 was not remarkable, unlike that for alpha-tocopherol, which implied different locations of radicals derived from BO-653 and alpha-tocopherol within the LDL particle. It was concluded that BO-653 protected LDL from oxidative modification efficiently by scavenging peroxyl radicals and by reducing alpha-tocopheroxyl radicals and that this novel antioxidant might act as a potent inhibitor of development of atherosclerosis.

Topics: Amidines; Animals; Antioxidants; Apolipoproteins B; Arteriosclerosis; Ascorbic Acid; Azo Compounds; Benzofurans; Cyclic N-Oxides; Drug Design; Free Radical Scavengers; Humans; Kinetics; Lipid Peroxidation; Lipid Peroxides; Lipoproteins, LDL; Nitriles; Oxidants; Oxidation-Reduction; Peroxides; Rabbits; Vitamin E

The hypocholesterolemic and antiatherosclerotic activities of FR145237, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, were evaluated in cholesterol-fed and Watanabe heritable hyperlipidemic (WHHL) rabbits. In the first experiment, rabbits were fed a high cholesterol (1% cholesterol) diet for 2 weeks and further fed a high cholesterol diet containing FR145237 for 8 weeks. FR145237 (0.1, 0.32 and 1.0 mg/kg) dose-dependently lowered the plasma total cholestrol levels by 80%, 96% and 97%, respectively. and reduced aortic atherosclerosis by 44%, 90% and 90%, respectively. To clarify a direct effect of FR145237 at the aortic wall, a second experiment was performed. Rabbits were fed a high-cholesterol diet for 8 weeks to establish aortic atherosclerosis and then fed a normal diet with or without FR145237 for 8 weeks. Cholesterol content in the aorta and the liver was significantly reduced in the FR145237 group (10 mg/kg) by 50% and 43%, respectively, though plasma total cholesterol level did not differ from that in the control group. In the WHHL rabbits, FR145237 (10 mg/kg) did not affect plasma cholesterol level but significantly reduced the atherosclerotic lesion in the coronary arteries by 61%. These results suggest that FR145237 potently lowers the plasma cholesterol level in hypercholesterolemia induced by dietary cholesterol but not that by LDL receptor deficiency, and that FR145237 has a direct antiatherosclerotic activity on the arterial wall independent of its hypocholesterolemic activity.

Topics: Animals; Aorta; Arteriosclerosis; Benzofurans; Carrier Proteins; Cholesterol; Cholesterol, Dietary; Diet, Atherogenic; Disease Models, Animal; Enzyme Inhibitors; Hypercholesterolemia; Hyperlipidemias; Lipoproteins, HDL; Lipoproteins, LDL; Liver; Male; Molecular Structure; Phenylurea Compounds; Rabbits; Receptors, Lipoprotein; RNA-Binding Proteins; Sterol O-Acyltransferase

We report the results of a pilot study to evaluate the therapeutical efficiency of Benzarone in a time span of four weeks in 11 male patients with intermittent claudication. Numerous experimental data indicate that there was a statistically significant increase of painless walking distance and a statistically significant decrease of plasma uric acid, cholesterol and triglycerides. Coagulation analyses furthermore show an increase of the factor VIII activity and the plasminogen levels. For the first time, positive results were shown with Benzarone in patients with intermittent claudication.

Topics: Arteriosclerosis; Benzbromarone; Benzofurans; Cholesterol; Factor VIII; Humans; Intermittent Claudication; Male; Middle Aged; Plasminogen; Triglycerides; Uric Acid

Local transmural electrical stimulation by chronically implanted electrodes of a carotid artery in rabbits was daily repeated. The area in direct contact to the electrodes covered 0.5 x 5 mm of adventitia. The carotid walls received DC impulses (10 ms/imp, 10 Hz, 100 microA) 2 x 1/2 h daily. Within 4 weeks a proliferate of smooth muscle cells develops in the intima at the spot where the anode contacts the outside of the artery. If the animals were fed 2% cholesterol in normal food the proliferate developed to a typical atheroma. The other parts of the arterial system did not develop plaques within this time. At the luminal side of the plaques no significant adhesions of platelets could be seen. Addition of 300 mg 2-ethyl-3-[-4-hydroxybenzoyl]-benzofuran (benzarone, Fragivix) to 100 g of animal food (containing 2% cholesterol) caused a less pronounced increase of serum cholesterol than in the controls which received cholesterol-containing food without benzarone. The development of plaques could not be prevented by benzarone, however, the growth of the atheromatous plaque was inhibited and the incorporation of lipids into the plaques was less pronounced than in those animals which received a diet with cholesterol but without benzarone. In those animals which received benzarone more lipid-laden foam cells were seen moving through the endothelium out of the plaque into the lumen of the stimulated artery. These foam cells were of mononuclear origin.

Topics: Animals; Anticholesteremic Agents; Arteriosclerosis; Benzbromarone; Benzofurans; Cholesterol; Electrodes, Implanted; In Vitro Techniques; Rabbits

Topics: Animals; Arteriosclerosis; Benzofurans; Iodobenzoates; Kidney; Liver; Rabbits; Vasodilator Agents

Topics: Aged; Arteriosclerosis; Benzofurans; Female; Humans; Male; Middle Aged; Retinal Degeneration; Retinal Diseases; Retinitis; Sclerosis; Vascular Diseases; Vasodilator Agents

Topics: Adult; Aged; Arteriosclerosis; Benzofurans; Female; Humans; Male; Middle Aged