Comparison of hypocholesterolemic activity for cyclic analogs of clofibrate in normolipemic rats

The synthesis of ethyl cis-6-chloro-4-hydroxychroman-2-carboxylate (IV) and 6-chloro-4-hydroxy-chroman-2-carboxylic acid lactone (V) are reported. The antilipidemic properties of these compounds in 3 rat models were compared to the activity obtained for the previously synthesized related analogs ethyl 6-chlorochroman-2-carboxylate (II), ethyl 6-chlorochromanone-2-carboxylate (III) and clofibrate (I). The biologically most interesting analog, ethyl 6-chlorochroman-2-carboyxlate (II) like clofibrate (I), was an effective antitriglyceridemic and anticholesterolemic agent in Triton WR-1339 hyperlipidemic rats, sucrose-fed hyperlipidemic rats and chow-fed normolipemic rats. Ethyl 6-chlorochromanone-2-carboxylate (III) was found to be active after 7 days of administration to sucrose-fed rats. In sucrose-fed, male Sprague-Dawley rats, the comparative effects of these analogs on various hepatic drug parameters also were carried out. Consistent with previous findings, results obtained with these compounds provide evidence showing that changes in hepatic HMG-CoA reductase activity bear no relationship to serum cholesterol lowering in the sucrose-fed model.

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“…Sucrose and normolipemic rat models (10,11). Methods were identical to those previously reported (2).…”

Section: Biological Methodsmentioning

confidence: 99%

“…Preparation of microsomes. The homogenization of livers and preparation of microsomes were done as described previously (4,11).…”

Section: Biological Methodsmentioning

confidence: 99%

Antilipidemic activity of 4‐oxo‐functionalized ethyl 6‐chlorochroman‐2‐carboxylate analogs and a related tricyclic lactone in three rat models

Cavestri

Minatelli

Baldwin

et al. 1981

Lipids

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“…In recent years, we have reported the comparative antilipidemic (10)(11)(12)(13) and antiaggregatory (14) activities of ethyl 6-chlorochroman-2-carboxylate (II), 6-phenylchroman-*Author to whom correspondence should be addressed.…”

Section: Thromboembolismmentioning

confidence: 99%

“…Livers were immediately excised, rinsed in ice-cold 0.1 M Tris-HC1 buffer, pH 7.2 (containing 1.15% KCI, w/v), blotted, weighed, minced and homogenized in the same buffer using a glass homogenizer equipped with a Teflon pestle. Liver microsomes were isolated as described previously (11).…”

Section: Experimental Designmentioning

confidence: 99%

Hypolipidemic effects of clofibrate and selected chroman analogs in fasted rats: II. High sucrose‐fed animals

Mukhopadhyay

Patel

O'Brien

et al. 1983

Lipids

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The hypolipidemic properties of ethyl 6-chlorochroman-2-carboxylate (II), 6-phenylchroman-2-carboxylate (III) and 6-cyclohexylchroman-2-carboxylate (IV) were compared to clofibrate (I) in sucrose-fed fasted male Sprague-Dawley rats. All compounds were administered at doses of 0.2 and 0.4 mmol/kg, orally, twice daily for 7 consecutive days. In this model, II was a more effective hypocholesterolemic drug than clofibrate, whereas III and IV were inactive. Chlorochroman II, like clofibrate, decreased serum alpha-lipoprotein cholesterol and pre-beta-lipoprotein triglyceride concentrations and concomitantly increased serum beta-lipoprotein triglyceride concentrations. In clofibrate-treated rats, serum free cholesterol concentrations increased concurrent with a reduction in serum lecithin: cholesterol acyltransferase activity, but no such correlation was observed for II. Only II lowered liver cholesterol levels and increased liver triglyceride levels. No consistent inhibition of liver microsomal 3-hydroxy-3-methylglutaryl-CoA reductase activity was observed with these analogs. The observed changes in triglyceride and cholesterol concentrations among serum lipoproteins were of a greater magnitude after chlorochroman II and clofibrate administration to sucrose-fed rats than in our previous studies using chow-fed fasted rats. These data suggest that chloro-substitution at the 6-position of the phenylchroman ring is important for hypolipidemic activity of these cyclic clofibrate analogs.

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“…The way in which clofibrate lowers the level of triglycerides is now well understood: it reduces fatty acids in the liver which reduces the synthesis of triglycerides and, consequently, the production and secretion of very low density lipoprotein (VLDL) (5). On the other hand, the hypocholesterolemic effect is not so well established; we khow it reduces the synthesis of hepatic cholesterol by inhibition of hydroxy methylglutaryl coenzyme A reductase and that it promotes the excretion of acid steroids in man (6) and rats (7)(8)(9)(10). The excretion of neutral steroids in rats remains unchanged (10) although the excretion of cholesterol through bile and feces in man is increased (1 1).…”

Section: Introductionmentioning

confidence: 99%

Effects of clofibrate and tiadenol on the elimination of lipids and bile acids in rat bile

Cuchet

Morrier

Cand

et al. 1981

Lipids

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The aim of the work presented here was to compare the biliary elimination of cholesterol and the different bile acids of rats that had been made hypolipidemic by short-term treatments with clofibrate or tiadenol. Both treatments induced a significant decrease in cholesterol output in the bile. The analysis of the different bile acids showed a decrease in dihydroxylated acids elimination (especially CDC acid) without any difference between the 2 sexes. This decrease was associated with an increase in cholic acid excretion. These results are directly correlated with the dose of the administered hypolipidemic drug. The drugs caused as significant increase in the ratio of trihydroxylated acids of the bile and on the output was obtained, for both drugs, with a treatment of 200 mg/kg/day. Clofibrate had a greater effect than tiadenol at this dose. Both drugs show a greater effect on lowering serum lipid levels in female animals when compared to males, whereas elimination of bile cholesterol and modifications of bile acids were greater in male animals than female animals.

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Comparison of hypocholesterolemic activity for cyclic analogs of clofibrate in normolipemic rats

Cited by 15 publications

References 30 publications

Antilipidemic activity of 4‐oxo‐functionalized ethyl 6‐chlorochroman‐2‐carboxylate analogs and a related tricyclic lactone in three rat models

Antilipidemic activity of 4‐oxo‐functionalized ethyl 6‐chlorochroman‐2‐carboxylate analogs and a related tricyclic lactone in three rat models

Hypolipidemic effects of clofibrate and selected chroman analogs in fasted rats: II. High sucrose‐fed animals

Effects of clofibrate and tiadenol on the elimination of lipids and bile acids in rat bile

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