Hypolipidemic activity of 3-amino-1-(2,3,4-mononitro-, mono-, or dihalophenyl)propan-1-ones in rodents.
A series of 3-amino-1-(2,3,4-mononitro-, mono-, or dihalo-phenyl)propan-1-ones were synthesized and shown to be effective in lowering both serum cholesterol and triglyceride levels significantly in CF1 mice and Sprague-Dawley rats. All analogs showed better activity than the standard drugs, lovastatin and clofibrate, in reducing the serum cholesterol and triglyceride levels in mice at 8 mg/kg/day intraperitoneally. The best active analogs, 3-morpholino-1(3-nitrophenyl)propan-1-one (4) and 3-piperidino-1-(3-nitrophenyl)propan-1-one (5), exhibited 58% and 67% reduction of serum cholesterol levels, respectively, and 42% and 46% reduction of serum triglyceride levels, respectively, after 16 days of administration at 8 mg/kg/day intraperitoneally in CF1 mice. In Sprague-Dawley rats at 8 mg/kg/day oral administration, both compounds (4 and 5) significantly decreased the serum cholesterol and triglyceride levels. Rat tissue lipid levels were reduced significantly by compound 4, while less effects resulted from compound 5. The cholesterol and triglyceride levels in chylomicrons, VLDL, and LDL fractions were reduced by both analogs while the HDL cholesterol levels were significantly increased. Compound 5 was also effective in lowering serum cholesterol and triglyceride levels in hyperlipidemic mice, at 8 mg/kg/day intraperitoneally, but not effective in hyperlipidemic rats at 8 mg/kg/day orally. Cholesterol and triglyceride lowering effects of the agents were correlated with inhibition of the activities of liver acetyl CoA synthetase, HMG CoA reductase, phosphatidylate phosphohydrolase, and lipoprotein lipase, and with elevation of the activity of cholesterol ester hydrolase.
Huang
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Y
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360, USA.
Hall
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IH
D000818:Animals; D002784:Cholesterol / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000097:blood
D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D007659:Ketones; D014280:Triglycerides; D002784:Cholesterol