benzofurans and Hyperlipidemias

Danshen, the dried root of Salvia miltiorrhiza, has been widely used in China and, to a lesser extent, in Japan, the United States, and other European countries for the treatment of cardiovascular and cerebrovascular diseases. In China, the specific clinical use is angina pectoris, hyperlipidemia, and acute ischemic stroke. The current review covers its traditional uses, chemical constituents, pharmacological activities, pharmacokinetics, clinical applications, and potential herb-drug interactions based on information obtained in both the English and Chinese literature. Although numerous clinical trials have demonstrated that certain Danshen products in China are effective and safe for the treatment of cardiovascular diseases, most of these lack sufficient quality. Therefore, large randomized clinical trials and further scientific research to determine its mechanism of actions will be necessary to ensure the safety, effectiveness, and better understanding of its action.

Topics: Abietanes; Angina Pectoris; Animals; Benzofurans; Drugs, Chinese Herbal; Fibrinolytic Agents; Herb-Drug Interactions; Humans; Hyperlipidemias; Lactates; Phenanthrenes; Phenanthrolines; Plant Extracts; Randomized Controlled Trials as Topic; Salvia miltiorrhiza; Stroke

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

The serum uric acid lowering effects of 100 mg Allopurinol (A), 20 mg Benzbromarone (B) and the combination of both were tested in a randomized block-trial in 12 male patients suffering from hyperuricemia and hyperlipoproteinemia type IIb/IV. Therapy periods lasted 4 weeks each. Allopurinol lowered the uric acid concentrations from 7,54 mg/100 ml to 5,95 mg/100 ml, Benzbromarone from 7,54 mg/100 ml to 6,11 mg/100 ml and the combination from 7,54 mg/100 ml to 4,90 mg/100 ml, all three significantly. The difference between the effect of the combination drug and Allopurinol and Benzbromarone respectively was also significant. An additive effect of both components is evident. Serum creatinin concentration remained constant. Uric acid and creatinin excretion could not be evaluated because of failure of patient compliance in the collecting of urine.

Topics: Adult; Allopurinol; Benzbromarone; Benzofurans; Drug Combinations; Humans; Hyperlipidemias; Male; Middle Aged; Triglycerides; Uric Acid

Topics: Animals; Aorta; Benzofurans; Cell Proliferation; Cells, Cultured; Chemokine CCL5; Diet, High-Fat; Disease Models, Animal; Hyperlipidemias; Hypolipidemic Agents; Male; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Phenotype; Receptors, CCR5; Signal Transduction; Tannins

ε-Viniferin (VNF), a naturally occurring oligostilbene (a resveratrol dimer), is mainly found in grapes and red wines. However, unlike resveratrol, the biological activity of VNF has not been widely studied. This study was conducted to investigate the beneficial effects of VNF on hyperglycemia and hyperlipidemia and further to reveal the underlying mechanism. The ameliorative effects of VNF in high-fat-diet and streptozotocin-induced type 2 diabetic rats were assessed physiologically, biochemically and histologically after oral administration of VNF (30 mg kg-1 and 60 mg kg-1) for 8 weeks. Western blotting and immunohistochemistry experiments were performed to determine the effects of VNF on the AMPK phosphorylation levels in the livers of diabetic rats. Molecular docking and molecular dynamics simulation were further performed to study the molecular-level interaction between VNF and AMPK. Meanwhile, the protective effects of VNF on the liver and kidney were also evaluated. The results showed that the VNF treatment caused a significant decrease in the concentrations of fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), and low density lipoprotein-cholesterol (LDL-C), and improved the glucose tolerance of diabetic rats. In addition, the liver and kidney damage indices such as alanine aminotransferase (ALT), aspartate aminotransaminase (AST), creatinine (CR), and blood urea nitrogen (BUN) were also lowered and improved. Moreover, VNF could increase the AMPK activation and attenuate histopathological changes in the liver of diabetic rats. The molecular docking and molecular dynamics simulation results revealed for the first time that VNF bound to the hinge region between the α- and β-units of AMPK and interacted with the active site of AMPK. In conclusion, VNF can effectively improve hyperglycemia and hyperlipidemia and exhibit protective effects on the liver and kidney functions. The underlying mechanism of VNF in hyperglycemia and hyperlipidemia may be related to the activation of AMPK in vivo. Our findings indicate that VNF is a potentially useful natural agent for the treatment of metabolic diseases, especially type 2 diabetes and hyperlipidemia.

Topics: AMP-Activated Protein Kinases; Animals; Benzofurans; Blood Glucose; Cholesterol, LDL; Diet, High-Fat; Humans; Hyperglycemia; Hyperlipidemias; Hypoglycemic Agents; Hypolipidemic Agents; Liver; Male; Rats; Rats, Sprague-Dawley; Stilbenes; Triglycerides

The lack of inclusion of comorbidities in animal models of stroke may underlie the limited development of therapy in stroke. Previous studies in mice deficient of CD36, an immune receptor, indicated its contribution to stroke-induced inflammation and injury in hyperlipidemic conditions. The current study, therefore, tested whether pharmacological inhibition of CD36 provides neuroprotection in hyperlipidemic stroke. The hyperlipidemic mice subjected to stroke showed an exacerbation of infarct size and profound brain swelling. However, post-stroke treatment with CD36 inhibitors did not reduce, and in some cases worsened, acute stroke outcome, suggesting potential benefits of elevated CD36 in the post-stroke brain in a hyperlipidemic condition. On the other hand, chronic treatment of a CD36 inhibitor prior to stroke significantly reduced stroke-induced brain swelling. There was a trend toward infarct reduction, although it did not reach statistical significance. The observed benefit of preventative CD36 inhibition is in line with previously reported smaller infarct volume and swelling in CD36 KO mice. Thus, the current findings suggest that insights gained from the genetic models should be carefully considered before the implementation of pharmacological interventions, as a potential therapeutic strategy may depend on preventative treatment or a post-stroke acute treatment paradigm.

Topics: Animals; Apolipoproteins E; Benzofurans; Brain Edema; CD36 Antigens; Disease Models, Animal; Drug Administration Schedule; Drugs, Chinese Herbal; Hyperlipidemias; Inflammation; Male; Mice, Inbred C57BL; Mice, Knockout; Protective Agents; Stroke

Obesity contributes to the development of cardiometabolic disorders such as type 2 diabetes, fatty liver disease and cardiovascular disease. Salvianolic acid B (Sal B) is a molecule derived from the root of Salvia miltiorrhiza (Danshen), which is a traditional Chinese medicine that is widely used to treat cardiovascular diseases. However, the role of Sal B in obesity and obesity-related metabolic disorders is unknown. In this study, we aimed to investigate the effects of Sal B on high-fat diet-induced obesity and determine the possible mechanisms involved.. Male C57BL/6J mice fed a high-fat diet for 12 weeks received a supplement of Sal B (100 mg/kg/day) by gavage for a further 8 weeks. These mice were compared to control mice fed an un-supplemented high-fat diet. 3T3-L1 preadipocytes were used in vitro studies.. Sal B administration significantly decreased body weight, white adipose tissue weight, adipocyte size and lipid (triglyceride and total cholesterol) levels in obese mice. Eight weeks of Sal B administration also improved the intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test (IPITT) scores in high-fat diet-induced obese mice. In 3T3-L1 preadipocytes that were cultured in vitro and induced to differentiate, Sal B reduced the accumulation of lipid droplets and lipid content in a dose-dependent manner. Immunoblotting indicated that Sal B decreased peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα) expression but increased the expression of GATA binding protein 2 and 3 (GATA 2, GATA 3) both in vivo and in vitro.. Our data suggest that Sal B may reduce obesity and obesity-related metabolic disorders by suppressing adipogenesis. The effects of Sal B in adipose tissue may be related to its action on PPARγ, C/EBPα, GATA-2 and GATA-3.

Topics: 3T3-L1 Cells; Animals; Benzofurans; Diet, High-Fat; Hyperlipidemias; Male; Mice; Mice, Inbred C57BL; Obesity; PPAR gamma; Weight Gain

Previous studies reported that exposure to dioxins was associated with an increased risk of various diseases in general populations.. The aim of this study was to examine the association between levels of dioxins in blood and allergic and other diseases.. We conducted a cross-sectional study on 1,063 men and 1,201 women (aged 15-76 years), who were living throughout Japan and not occupationally exposed to dioxins, during 2002-2010. In fasting blood samples, polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like PCBs (DL-PCBs) were analyzed by isotope dilution high-resolution gas chromatography/mass spectrometry. We obtained information on life style and self-reported history of diseases using a questionnaire. Blood pressure, blood levels of hemoglobin A1c, and serum lipids were also measured. Multiple logistic regression models were used to analyze the association between dioxin levels in blood and various diseases.. Toxic equivalents of PCDDs/PCDFs and total dioxins showed significant inverse dose-response relationships with atopic dermatitis, after adjustments for potential confounders. The highest quartile for total dioxins had an adjusted odds ratio of 0.26 (95 % confidence interval 0.08-0.70) compared to the reference group (first quartile). The odds ratios for hypertension, diabetes mellitus, hyperlipidemia, gout in men, and gynecologic diseases in women significantly increased with increasing toxic equivalents of PCDDs/PCDFs, DL-PCBs, and total dioxins in blood.. The present findings suggest that background exposure to dioxins was associated with reduced risk of atopic dermatitis. The results also support the idea that low-level exposure to dioxins is associated with an increased risk of diabetes, hypertension, and hyperlipidemia.

Topics: Adolescent; Adult; Aged; Benzofurans; Cross-Sectional Studies; Dermatitis, Atopic; Diabetes Mellitus; Environmental Exposure; Female; Humans; Hyperlipidemias; Hypertension; Japan; Life Style; Male; Middle Aged; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Surveys and Questionnaires; Young Adult

CD36, a class B scavenger receptor, has been implicated in the pathogenesis of a host of vascular inflammatory diseases. Through a high-throughput screening (HTS) assay for CD36 antagonist, we previously identified salvianolic acid B (SAB), a hydrophilic component derived from the herb Danshen, as a potential candidate. Danshen, the dried roots of Salvia miltiorrhiza, has been widely used in China for the prevention and treatment of atherosclerosis-related disorders. Previous studies showed that SAB acted as an anti-oxidant by preventing lipid peroxidation and oxidized LDL (oxLDL) formation. The present study was to investigate the specificity and efficacy of SAB in the inhibition of CD36-mediated lipid uptake. SAB reduced modified LDL (mLDL) uptake in a dose-dependent manner in phorbol-12-myristate-13-acetate (PMA)-stimulated THP-1 and RAW 264.7 cells. In the CD36 silenced THP-1 cells, SAB had no effect in reducing mLDL uptake, whereas its overexpression in CHO cells reinstates the effect, indicating a specific involvement of SAB in antagonizing the CD36's function. Surface plasmon resonance (SPR) analysis revealed a direct binding of SAB to CD36 with a high affinity (K(D) = 3.74 μM), confirming physical interactions of SAB with the receptor. Additionally, SAB reduced oxLDL-induced CD36 gene expression in the cultured cell lines and primary macrophages. In ApoE KO mice fed a high fat diet, SAB reduced CD36 gene expression and lipid uptake in macrophages, showing its ability to antagonize CD36 pathways in vivo. These results demonstrate that SAB is an effective CD36 antagonist and suggest SAB as a potential anti-atherosclerotic agent.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Benzofurans; Biological Transport; CD36 Antigens; Cell Line, Tumor; CHO Cells; Cricetinae; Cricetulus; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Hyperlipidemias; Hypolipidemic Agents; Lipoproteins, LDL; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, LDL; RNA Interference; Surface Plasmon Resonance; Tetradecanoylphorbol Acetate; Time Factors; Transfection

Using Triton WR-1339-induced hyperlipidemic rats as an experimental model, we investigated whether compound 4 [N-(9,10-dihydro-9,10-dioxoanthracen-2-yl)benzofuran-2-carboxamide] and compound 5 [N-(4-benzoylphenyl)benzofuran-2-carboxamide], two novel anti-hyperlipidemic agents, have any effect on plasma triglyceride (TG), total cholesterol (TC), and high-density lipoprotein cholesterol levels (HDL-C) levels. The tested animals were divided into control (CG), hyperlipidemic (HG), and compounds 4, 5, and bezafibrate (BF) treated groups. At a dose of 15 mg/kg body weight, compounds 4, 5, and BF significantly reduced elevated plasma TG levels after 7 and 24 h. Furthermore, HDL-C levels were remarkably increased in all treated groups after 7 and 24 h compared to the hyperlipidemic control group. However, only compounds 4 and 5 treated groups clearly showed a significant reduction in plasma total cholesterol levels after 7 and 24 h. It is therefore reasonable to assume that compounds 4 and 5 may have promising potential in the treatment of hyperlipidemia and atherosclerosis.

Topics: Animals; Anthracenes; Atherosclerosis; Benzofurans; Bezafibrate; Cholesterol; Cholesterol, HDL; Detergents; Drug Design; Hyperlipidemias; Hypolipidemic Agents; Lipids; Male; Molecular Structure; Polyethylene Glycols; Random Allocation; Rats; Rats, Wistar; Time Factors; Triglycerides

We conducted this study to isolate novel anti-hyperlipidemic agents derived from natural marine products. To accomplish this, we investigated the effects of ethanolic (EtOH) extracts of Ecklonia stolonifera and its phlorotannin constituents, eckol and dieckol, on serum lipid levels in rats with hyperlipidemia that was induced by a high-cholesterol diet or poloxamer 407. Treatment with the EtOH extracts of E. stolonifera and its phlorotannin-rich ethyl acetate (EtOAc) and n-butanol (n-BuOH) fractions induced a significant reduction in triglycerides (TG), total cholesterol (TC), and low-density lipoprotein-cholesterol (LDL-C) levels, as well as a significant increase in the high-density lipoprotein-cholesterol (HDLC) level in hyperlipidemic rats. However, treatment with the water (H(2)O) fraction did not exert any significant effects on the serum levels of hyperlipidemic rats. In addition, eckol and dieckol isolated from the active EtOAc fraction induced a significant reduction in serum TG, TC, and LDL-C levels, as well as in the atherogenic index (A.I.). Furthermore, treatment with dieckol induced a greater decrease in the serum TG, TC, and LDL-C levels of hyperlipidemic rats than eckol or lovastatin, as well as an increase in the serum HDL-C levels. Taken together, these results suggest that phlorotannins such as eckol and dieckol have the potential for use for the prevention of hyperlipidemic atherosclerosis.

Topics: Animals; Benzofurans; Cholesterol, Dietary; Diet; Dioxins; Ethanol; Freeze Drying; Hyperlipidemias; Hypolipidemic Agents; Male; Phaeophyceae; Poloxamer; Rats; Rats, Sprague-Dawley; Solvents; Tannins; Triglycerides

It has been hypothesized that oxidative modification of low density lipoprotein plays a key role in the pathogenesis of atherosclerosis. In order to elucidate the role of lipid oxidation and its inhibition in vivo, apolipoprotein E and alpha-tocopherol (alphaT) transfer protein double knockout (ApoE(-/-)alpha-TTP(-/-)) and apolipoprotein E knockout (ApoE(-/-)) mice fed with a vitamin E-depleted diet and a diet containing 0.002 wt.% alphaT, respectively, were used with or without the treatment of a synthetic antioxidant 2,3-dihydro-5-hydroxy-4,6-di-tert-butyl-2,2-dipentylbenzofuran (BO-653, 0.2 wt.%). The lipid oxidation markers of total hydroxylinoleic acid (tHODE), 8-iso-prostaglandin F(2alpha), and 7-hydroxycholesterol (t7-OHCh) in the blood, liver, and brain were inclusively measured with or without an excessive cholesterol-feeding (Ch-diet). The tHODE levels were elevated by Ch-diet in the plasma and brain of ApoE(-/-)alpha-TTP(-/-) mice and in the liver of ApoE(-/-) mice without BO-653. The levels of t7-OHCh in the liver were also increased due to the Ch-diet, and the ratio of t7-OHCh to the parent compound cholesterol was reduced to the control levels by BO-653. In summary, it was demonstrated by biomarkers, tHODE and t7-OHCh, that the added BO-653 in their diets exerted antioxidative effects in vivo under the condition of reduced vitamin E.

Topics: alpha-Tocopherol; Animals; Apolipoproteins E; Benzofurans; Brain; Carrier Proteins; Erythrocytes; Fatty Acids, Unsaturated; Hydroxycholesterols; Hyperlipidemias; Hypolipidemic Agents; Lipid Peroxidation; Liver; Male; Mice; Mice, Inbred C57BL

The design and synthesis of a novel class of 2,3-dihydrobenzofuran-2-carboxylic acids as highly potent and subtype-selective PPARalpha agonists are reported. Systematic study of structure-activity relationships has identified several key structural elements within this class for maintaining the potency and subtype selectivity. Select compounds were evaluated in animal models of dyslipidemia using Syrian hamsters and male Beagle dogs, and all these compounds displayed excellent cholesterol- and triglyceride-lowering activity at dose levels that were much lower than the marketed weak PPARalpha agonist fenofibrate.

Topics: Animals; Benzofurans; Carboxylic Acids; Cholesterol; Cricetinae; Dogs; Humans; Hyperlipidemias; Hypolipidemic Agents; In Vitro Techniques; Male; Mesocricetus; Molecular Conformation; PPAR alpha; Radioligand Assay; Stereoisomerism; Structure-Activity Relationship; Transcriptional Activation; Triglycerides

The adrenal toxicity of an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, FR145237, was investigated using Japanese White (normal) and low density lipoprotein (LDL) receptor deficient Watanabe heritable hyperlipidemic (WHHL) rabbits. In the normal rabbits, severe necrosis of the cells in the zona fasciculata and reticularis was observed 24 hr after intravenous injection of 3.2 mg/kg of FR145237, whereas no morphological changes could be found in the adrenal cells of the WHHL rabbits in spite of a higher plasma concentration of the drug. Since most of the FR145237 (87%) in the plasma of the WHHL rabbits was recovered in the LDL fraction 1 hr after intravenous injection of the drug (3.2 mg/kg), it was hypothesized that the delivery of the drug to the adrenal cells may be limited by the LDL receptor deficiency. However, the concentration of FR145237 in the adrenal gland of the WHHL rabbits (13.3 microg/g) was identical to that in the normal rabbits (13.6 microg/g). These results suggest that the susceptibility of the adrenal cells of the WHHL rabbits to the toxicity of FR145237 truly differs from that of normal rabbits, and that the WHHL rabbit may be a useful animal model for the investigation of the mechanisms of the adrenal toxicity of ACAT inhibitors.

Topics: Adrenal Cortex; Adrenal Cortex Diseases; Animals; Benzofurans; Disease Susceptibility; Hyperlipidemias; Phenylurea Compounds; Rabbits; Receptors, LDL; Species Specificity; Sterol O-Acyltransferase

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

Serum lipid levels in rats with hyperlipidemia induced by diet as well as by Triton were determined after oral administration of EtOAc extract of Pterocarpus marsupium heartwood and its flavonoid constituents, marsupsin [1], pterosupin [2], and liquiritigenin [3]. Administration of EtOAc extract for 14 consecutive days produced a significant reduction of serum triglyceride, total cholesterol, and LDL- and VLDL-cholesterol levels without any significant effect on the level of HDL-cholesterol. Liquiritigenin and pterosupin were able to effect a significant fall in serum cholesterol, LDL-cholesterol, and atherogenic index, pterosupin being additionally effective in lowering serum triglyceride.

Topics: Animals; Anticholesteremic Agents; Benzofurans; Cholesterol; Cresols; Diet; Flavanones; Flavonoids; Glucosides; Hyperlipidemias; Hypolipidemic Agents; Lipids; Male; Phenols; Plant Extracts; Plants; Polyethylene Glycols; Rats; Triglycerides

Topics: Aged; Amiodarone; Benzofurans; Humans; Hyperlipidemias; Male

The antilipidemic properties of diethyl (4balpha,4calpha,9aalpha,4balpha)-3,6-dichlorocyclobutal[1,2-b:3,4-b']bisbenzofuran-9a,9b(4bH,4cH)-dicarboxylate, herein termed dimer 8, were studied in sucrose-fed and in Triton-induced hyperlipidemic rats. Whereas clofibrate (0.4 mmol/kg) exhibited both anticholesterolemic and antitriglyceridemic activity, dimer 8 showed only antitriglyceridemic properties at the lower dose (0.2 mmol/kg) in sucrose-fed rats. Dimer 8 only lowered serum triglycerides levels in Triton WR-1339 hyperlipidemic rats, whereas clofibrate lowered both cholesterol and triglyceride levels. In the chronic sucrose-fed model, dimer 8 and clofibrate lowered hepatic HMG-CoA reducatase activity and produced significant elevations in several parameters of hepatic drug metabolism. No positive relationship between serum cholesterol lowering and reduction of hepatic HMG-CoA reductase activity was observed by these agents in sucrose-fed rats.

Topics: Animals; Benzofurans; Cholesterol; Clofibrate; Cyclobutanes; Ethylmorphine-N-Demethylase; Hydroxymethylglutaryl CoA Reductases; Hyperlipidemias; Hypolipidemic Agents; Liver; Male; Microsomes, Liver; Molecular Conformation; NADPH-Ferrihemoprotein Reductase; Organ Size; Rats; Sucrose; Triglycerides

Topics: Animals; Benzofurans; Chemical Phenomena; Chemistry; Cholesterol; Drug Evaluation, Preclinical; Glycolates; Hyperlipidemias; Hypolipidemic Agents; Lipids; Male; Phenoxyacetates; Rats; Structure-Activity Relationship; Time Factors; Triglycerides

Topics: Animals; Benzofurans; Chemical Phenomena; Chemistry; Clofibrate; Drug Evaluation, Preclinical; Hyperlipidemias; Hypolipidemic Agents; Lipids; Propionates; Rats; Structure-Activity Relationship; Time Factors

The antilipidemic properties of certain benzofuran-, 2,3-dihydrobenzofuran-, and 3(2H)-benzofuranone-2-carboxylate analogs of clofibrate in a hyperlipidemic rat model are described. The hyperlipidemia was induced by intraperitoneal injection of Triton WR-1339. The results were analyzed in light of structural modifications as well as the lipid solubility of substituted compounds as assessed by a consideration of calculated log P values. Comparisons are made between the activity of these compounds and the activity of related cyclic analogs previously reported. Among the various compounds tested, only the 5-C1 and phenylsybstituted dihydrobenzofurans were selective against elevated serum cholesterol levels in this animal model. The data presented support the hypothesis that the cholesterol and triglyceride lowering activity of clofibrate related analogs in this animal model may be separated through a consideration of log P, conformational, and electronic changes. The proposal is advanced that relatively minor structural modification of clofibrate related analogs may lead to compounds which are not only selective in the Triton model but also to compounds which are likely to exert their effects by differing modes of action.

Topics: Animals; Benzofurans; Clofibrate; Hyperlipidemias; Hypolipidemic Agents; Magnetic Resonance Spectroscopy; Polyethylene Glycols; Rats; Structure-Activity Relationship

Topics: Adult; Allopurinol; Anemia; Arthritis; Benzofurans; Gout; Humans; Hyperlipidemias; Hypothyroidism; Hypoxanthines; Kidney Calculi; Male; Metabolism, Inborn Errors; Pedigree; Pentosyltransferases; Uric Acid; Uricosuric Agents

Topics: Animals; Anticholesteremic Agents; Benzene Derivatives; Benzofurans; Benzopyrans; Carboxylic Acids; Cholesterol; Clofibrate; Densitometry; Dioxins; Disease Models, Animal; Electrophoresis; Esters; Hyperlipidemias; Hypolipidemic Agents; Lipids; Lipoproteins; Male; Rats; Structure-Activity Relationship; Surface-Active Agents; Triglycerides

Topics: Adult; Benzofurans; Blood Glucose; Blood Sedimentation; Colchicine; Creatinine; Diabetes Mellitus; Electrocardiography; Fatty Liver; Female; Gout; Humans; Hyperlipidemias; Hypertension; Lipids; Liver Function Tests; Male; Middle Aged; Uric Acid