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

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.

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.

Synthesis and pharmacological evaluation of a clofibrate-related tricyclic spirolactone, 5-chloro-4',5-dihydrospiro[benzofuran-2(3H),3'(2'H)-furan]-2'-one.

The chemistry and pharmacology of the title compound, spirolactone 4, are reported. The synthesis represents a new approach to the preparation of spiro compounds. The pharmacological profiles of 4 are compared to that of clofibrate in Triton-induced hyperlipidemic, sucrose-fed, and normal Sprague-Dawley rat models. Clofibrate was effective in all animal models, but the spirolactone 4 exhibited antitriglyceridemic activity only in the Triton model. The inactivity of 4 in sucrose- and chow-fed rats could not be attributed to a resistance to hydrolysis by serum esterases. Comparative studies revealed that inhibition of hepatic HMG-CoA reductase activity may not be an index of hypocholesterolemic action in sucrose-fed rats. Additionally, only clofibrate exhibited significant changes in components of the hepatic microsomal monooxygenase system.

Diethyl (4baalpha,4calpha,9aalpha,9balpha)-3,6-dichlorocyclobuta[1,2-b:3,4-b']bisbenzofuran-9a,9b(4bH,4cH)-dicarboxylate: the cis,syn photodimer of ethyl 5-chlorobenzofuran-2-carboxylate, an analogue related to the antilipidemic drug clofibrate.

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.