3-Alkyl-3-hydroxyglutaric acids: a new class of hypocholesterolemic HMG CoA reductase inhibitors. 1.
Derivatives of 3-hydroxy-3-methylglutaric acid (HMG), a portion of the substrate for HMG CoA reductase, were prepared and tested for their inhibitory action against rat liver HMG CoA reductase and for their hypocholesterolemic activity. Structure-dependent competitive inhibition was observed. Optimal structures had a free dicarboxylic acid with an alkyl group of 13-16 carbons at position 3. 3-n-Pentadecyl-3-hydroxyglutaric acid (3j) (IC50 = 50 microM) reduced serum cholesterol in the Triton-treated rat and HMG CoA reductase activity in the 20,25-diazacholesterol-treated rat.
D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis*; D001373:Azacosterol / Q000494:pharmacology; D005977:Glutarates / Q000138:chemical synthesis* / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D000924:Anticholesteremic Agents; D005977:Glutarates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011092:Polyethylene Glycols; D001373:Azacosterol