Synthesis of ethyl 6-substituted-chroman- and -chromone-2-carboxylates. A comparative structure-activity study employing the 6-phenyl and phenoxy analogs in the triton hyperlipidemic rat model.
To explore the effect of lipophilicity on antilipidemic activity in the Triton WR-1339 induced hyperlipidemic rat model we synthesized the 6-cyclohexyl, phenyl, and phenoxy analogs of ethyl chroman-2-carboxylate. Results obtained were analyzed in light of the biological activity observed for the 6-chloro-substituted and unsubstituted chromans, the 6-chlorochroman-4-one ester, and the 6-chloro-, phenyl-, and phenoxychromone esters. The suggestion is made that chromones likely exert their antilipidemic effects by a somewhat different set of mechanisms than do the chromans and clofibrate. Whereas the 6-chlorochromanone ester is inactive, the 6-chlorochromone ester is active in both normal and hyperlipidemic Sprague-Dawley rats. The major differential effect was observed for ethyl 6-cyclohexylchroman-2-carboxylate which did not lower cholesterol levels but returned triglyceride levels to normal in hyperlipidemic rats.
D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000627:therapeutic use; D002784:Cholesterol / Q000097:blood; D002839:Chromans / Q000138:chemical synthesis* / Q000627:therapeutic use; D002867:Chromones / Q000138:chemical synthesis* / Q000627:therapeutic use; D004195:Disease Models, Animal; D006868:Hydrolysis; D006949:Hyperlipidemias / Q000139:chemically induced / Q000188:drug therapy*; D007700:Kinetics; D008297:Male; D011092:Polyethylene Glycols; D000644:Quaternary Ammonium Compounds; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood
D001578:Benzopyrans; D002264:Carboxylic Acids; D002839:Chromans; D002867:Chromones; D000644:Quaternary Ammonium Compounds; D014280:Triglycerides; D011092:Polyethylene Glycols; D002784:Cholesterol