Hypolipidemic effects of clofibrate and selected chroman analogs in fasted rats: II. High sucrose-fed animals.
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.
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002839:Chromans / Q000494:pharmacology*; D002994:Clofibrate / Q000494:pharmacology*; D004041:Dietary Fats; D005215:Fasting; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D007700:Kinetics; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013395:Sucrose / Q000378:metabolism*
D001578:Benzopyrans; D002839:Chromans; D004041:Dietary Fats; D008074:Lipoproteins; D013395:Sucrose; D006903:Hydroxymethylglutaryl CoA Reductases; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D002994:Clofibrate