9-Chloro-2,3-dihydro-5H-1,4-dioxepino[6,5-b]benzofuran, a novel antilipidemic agent structurally related to clofibrate

Abstract

The synthesis and antilipidemic activity of 9-chloro-2,3-dihydro-5H-1,4-dioxepino[6,5-b]benzofuran (3), a novel enol lactone which is considerably more resistant to serum esterase hydrolysis than clofibrate (1), are discussed. Whereas both 3 and 1 reduced hypercholesterolemic and hypertriglyceridemic serum levels in the Triton WR-1339 induced hyperlipidemic Sprague-Dawley rat to normal, the hydrolysis product of 3, namely 5-chloro-3(2'-hydroxyethoxy)-2-benzofurancarboxylic acid (4), was found to be inactive. Further, 3 is comparable to the hydrolysis product of 1 when both were assessed for their ability to block norepinephrine (NE) induced lipolysis in vitro. 4 is inactive at comparable concentrations (5 times 10(-4)-10(-3) M). The antilipidemic action of 3 and 1 may, in part, be due to their ability to block NE-induced lipolysis.

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

“…Hydrolysis of 2 and 4 in Rat Serum. The hydrolysis observed for clofibrate (2) and spirolactone 4 during incubation with rat serum at 37 °C was >90% after 5 min.…”

“…We previously reported the synthesis and antilipidemic properties for enol lactone 1, an analogue found to be considerably more resistant to serum esterase hydrolysis than clofibrate (2) in vitro. 2 Tricyclic analogue 1 compared favorably2 with 2 in reducing serum cholesterol and triglyceride levels in the Triton WR-1339 induced hyperlipidemic rat model.3 However, in normolipemic rats 1 had no hypocholesterolemic activity, whereas 2 was active in such animals.…”

“…We previously reported the synthesis and antilipidemic properties for enol lactone 1, an analogue found to be considerably more resistant to serum esterase hydrolysis than clofibrate (2) in vitro. 2 Tricyclic analogue 1 compared favorably2 with 2 in reducing serum cholesterol and triglyceride levels in the Triton WR-1339 induced hyperlipidemic rat model.3 However, in normolipemic rats 1 had no hypocholesterolemic activity, whereas 2 was active in such animals. 4 Since it was proposed that the antilipidemic properties of 2 are related to the rapid formation in vivo of the hydrolysis product 3,5 the differential effects of 1 in the two animal models may reflect a resistance to hydrolysis in vivo.…”

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

“…While the 5-chloro-and 5-phenyldihydrobenzofurans selectively lowered elevated cholesterol levels in Triton-induced hyperlipidemic rats (5), 6-substituted-chromans (3) and a clofibrate-related tricyclic enol-lactone (22) like clofibrate, showed both anticholesterolemic and antitriglyceridemic activities at the same dose (0.124 mmol/kg) in this model. However, at 89 this dose, both clofibrate and the enol-lactone only exhibited antitriglyceridemic activity (22). These findings are not unlike most other analogs of clofibrate synthesized in our laboratories, including IV and V, which at the 0.124 mmol/kg dose exhibited selective antitriglyceridemic activity in Tritoninduced hyperlipidemic rats.…”

Comparative antilipidemic effects of various ethyl 5‐substituted benzofuran‐, 2,3‐dihydrobenzofuran‐, and 3(2H)‐benzofuranone‐2‐carboxylate analogs of clofibrate in a triton hyperlipidemic rat model

“…In this case, the chloro analog (X), having the lowest log P value, seems to be most effective against elevated triglyceride levels. Since 3-keto analo~ exist in equilibrium with their enol forms (35), these compounds are expected to have markedly different electronic properties than the corresponding dihydrobenzofurans. Enol formation is in part stabilized owing to the generation of a n-excessive heteroaromatic ring system not unlike the hetero ring found in the benzofurans.…”