Synthesis and Pharmacological Studies of 3‐Amino‐2‐methyl‐1‐phenylpropanones as Hypolipidemic Agents in Rodents

Abstract

A series of 3‐amino‐2‐methyl‐1‐phenylpropanones were synthesized and proven to have potent hypolipidemic activity in rodents by lowering both serum cholesterol and triglyceride levels at 8 mg/kg/day, i.p. and orally. Many of these analogs showed significantly higher activity than standard drugs, lovastatin and clofibrate at their therapeutic doses. 2‐Methyl‐3‐(perhydroazepin‐1‐yl)‐1‐phenylpropanone (@!4), 3‐(4‐methylpiperazin‐1‐yl)‐1‐phenylpropanone (5), and 2‐methyl‐3‐(4‐pyrrolidinocarbonyl‐methylpiperazin‐1‐yl)‐1‐(4‐fluorophenyl) propanone (17) showed the best overall activities in lowering both serum cholesterol and triglyceride levels in CF₁ mice at 8 mg/kg/day after 16 days of treatment. Compounds 4, 5, and 17 lowered serum cholesterol levels 63%, 58%, and 42%, respectively, after 16 days at 8 mg/kg/day i.p. These agents reduced the serum triglyceride levels by 33%, 37%, and 54%, respectively. In Sprague‐Dawley rats these compounds also demonstrated significant serum lipid lowering effects by decreasing both serum cholesterol and triglyceride levels after 14 days of oral drug administration at 8 mg/kg/day. Compound 17 reduced the rat aorta cholesterol levels by 37%, triglyceride levels by 50%, and neutral lipid levels by 34% after 14 days of oral administration. These compounds lowered the chylomicron, VLDL, and LDL cholesterol and triglyceride levels while elevating the HDL cholesterol levels significantly. In hyperlipidemic rodents, these analogs also demonstrated significant serum lipid lowering effects but were less active than in normalipidemic rodents. The activities of some enzymes, such as mouse hepatic acetyl CoA synthetase, HMG CoA reductase, phosphatidylate phosphohydrolase, and hepatic lipoprotein lipase, were significantly reduced by these compounds.