Synthesis and pharmacological evaluation of cis-3,4,4a,9a-tetrahydro-1H-pyrano[3,4-b]benzofuran-1-ones. Tricyclic analogues related to the antilipidemic drug clofibrate.
The chemistry and pharmacology of two delta-lactones, cis-6-chloro-9a-methyl-3,4,4a,9a-tetrahydro-1H-pyrano[3,4-b]benzofuran-1-one (2) and the 9a-demethyl analogue 3, are reported. Lactones were prepared from dihydrobenzofuran precursors possessing geometrical configurations confirmed both by synthesis and 1H NMR spectroscopy. All cis-dihydrobenzofurans exhibited Jvic = 9.0-10.8 Hz, whereas their trans isomers exhibited Jvic = 5.0--6.0 Hz in agreement with predictions based on the Karplus equation. The pharmacological profiles for 2 and 3 were compared to that of clofibrate (1) in normal male Sprague-Dawley rats. Using equimolar doses (0.4 mmol/kg, po, twice daily for 7 days), 1 exhibited both anticholesterolemic and antitriglyceridemic activity, lactone 2 exhibited only antitriglyceridemic activity, and 3 was inactive as an antilipidemic agent. No correlation was observed for inhibition of hepatic HMG-CoA reductase activity and serum cholesterol lowering.
D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D002994:Clofibrate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D005037:Ethylmorphine-N-Demethylase / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones / Q000138:chemical synthesis / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D051381:Rats; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
D001572:Benzofurans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones; D014280:Triglycerides; D002784:Cholesterol; D005037:Ethylmorphine-N-Demethylase; D009251:NADPH-Ferrihemoprotein Reductase; D002994:Clofibrate