Synthesis of Benzothiophene Carboxamide Derivatives and their Pharmacological Evaluation as Potent Antihypertriglyceridemic Agents in Rats

There is a great deal of experimental, epidemiological, and clinical evidence suggesting that hyperlipidemia plays an important role in the pathogenesis of atherosclerosis and cardiovascular diseases (Goldstein et al., 1973; Frishman, 1998). This lipid metabolism disorder is characterized by elevated concentrations of circulating lipids including triglycerides, total cholesterol, very low-density lipoprotein, and low-density lipoprotein (Raasch, 1988). Hyperlipidemia is usually asymptomatic and is regularly detected during routine screening. The increased incidence of cardiovascular disease (CVD) among patients with elevated concentrations of circulating lipids has led to increased recognition of hyperlipidemia as important targets of therapy. In the course of the present study, Triton WR1339-induced hyperlipidemic rats were used as an experimental model to investigate the potential activity of some synthetic hypolipidemic agents. Previous studies showed that a single parenteral administration of Triton WR-1339 to adult rats produces hyperlipidemia in which cholesterol, triglycerides, and phospholipids levels increase to a maximum within about 20 hours and decrease thereafter (Schurr et al., 1972). This activity of Triton WR-1339 was found to be due to its inhibitory effect on lipoprotein lipase (Schotz et al., 1957). Currently hyperlipidemia is treated with different groups of drugs including fi brates and their derivatives (such as bezafi brate) (Frick et al., 1987). Fibric acids enhance the fatty acid catabolism and accordingly reduce plasma lipid levels, predominantly triglyceride levels (Rubins et al., 1999). The main mechanism was found to be through decreasing the synthesis of apoC-III and increasing the activity of lipoprotein lipase, which together enhance the clearance of circulating triglyceride-rich lipoproteins (Schoonjans et al., 1996). Benzothiophene and its derivatives have been reported to show activity in treating various medical conditions, such as hyperlipidemia, breast cancer, and uterus cancer (Charles et al., 1984). On the other hand, other groups of compounds such as benzophenone, aminopyridine, and amiSynthesis of Benzothiophene Carboxamide Derivatives and their Pharmacological Evaluation as Potent Antihypertriglyceridemic Agents in Rats Ghassan Abu Sheikha, Buthina Hussin, Yusuf Al-Hiari, Tariq Al-Qirim*, and Ghassan Shattat