Synthesis and hypolipidemic evaluation of beta-alkylaminopropiophenone and beta-alkylaminopropio-2'-naphthone derivatives in rodents.

A series of beta-alkylamino-(4'-alkyl)-propiophenone or beta-alkylamino(7'-methyl)-propio-2'-naphthone derivatives were prepared and found to have hypolipidemic activity by lowering both serum cholesterol and triglyceride levels in rodents. The electron donating substituent at the para position of the phenyl ring seems to decrease the hypolipidemic activity when compared to non-substituted or electron withdrawing group substituted analogs as investigated previously in this laboratory. In comparison with lovastatin or clofibrate, most of these analogs showed similar or higher activity in lowering both serum cholesterol or triglyceride levels. beta-Pyrrolidino-(4'-methyl)-propiophenone (1) demonstrated the best activity after 16 d, i.p. administration in mice at 8 mg/kg/d. Further detailed studies in rats indicated that beta-pyrrolidino-(4'-methyl)-propiophenone also showed decreased serum cholesterol and triglyceride levels with increased HDL-cholesterol and triglyceride levels after 14 d. In hyperlipidemic mice and rats, this compound was observed to be effective in lowering serum lipid levels as well as tissue lipid levels. The activities of hepatic acetyl CoA synthetase, phosphatidylate phosphohydrolase, and hepatic lipoprotein lipase were moderately inhibited by beta-pyrrolidino-(4'-methyl)-propiophenone.