Hypolipidemic effects of 6-amino-2-mercapto-5-methylpyrimidine-4-carboxylic acid in rats and tissue culture cells.
6-Amino-2-mercapto-5-methylpyrimidine-4-carboxylic acid (AMMPCA) was found to be a potent hypolipidemic agent at oral doses of 10 and 20 mg/kg/day in rodents. This agent was observed to affect de novo lipid synthesizing enzyme activities in a manner that resulted in lower lipid levels in tissues including the aorta wall. Very low density lipoprotein and low density lipoprotein cholesterol levels were reduced, whereas high density lipoprotein cholesterol levels were significantly increased. AMMPCA interfered with low density receptor activity, suggesting that the drug blocked lipid uptake by peripheral tissue while stimulating binding of lipid to the high density lipoprotein receptor, which should accelerate lipid clearance from the tissues and blood. A second mode of action of the drug is enhanced biliary excretion of lipids, but there was no evidence of a lithogenic effect. Acute toxicity studies in rodents support the fact that AMMPCA is safe in its therapeutic dose range.
Hall
I H
IH
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360.
Wong
O T
OT
Reynolds
D J
DJ
Simlot
R
R
Chang
J J
JJ
D000818:Animals; D001059:Apoproteins / Q000032:analysis / Q000378:metabolism; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004435:Eating; D005298:Fertility / Q000187:drug effects; D005347:Fibroblasts; D006801:Humans; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D007408:Intestinal Absorption; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000096:biosynthesis / Q000097:blood; D008075:Lipoproteins, HDL / Q000096:biosynthesis; D008077:Lipoproteins, LDL / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009929:Organ Size / Q000502:physiology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
D001059:Apoproteins; D000960:Hypolipidemic Agents; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D011743:Pyrimidines; C070934:6-amino-2-mercapto-5-methylpyrimidine-4-carboxylic acid