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.