3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 1. Structural modification of 5-substituted 3,5-dihydroxypentanoic acids and their lactone derivatives.
A series of 5-substituted 3,5-dihydroxypentanoic acids and their derivatives have been prepared and tested for inhibition of HMG-CoA reductase in vitro. In general, unless a carboxylate anion can be formed and the hydroxy groups remain unsubstituted in an erythro relationship, inhibitory activity is greatly reduced. Furthermore, only one enantiomer of the ring-opened form of lactone 6a(+/-) possesses the activity displayed by the racemate. Insertion of a bridging unit other than ethyl or (E)-ethenyl between the 5-carbinol moiety and an appropriate lipophilic moiety (e.g., 2,4-dichlorophenyl) attenuates activity.
D006018:Glycols / Q000138:chemical synthesis / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones / Q000138:chemical synthesis / Q000494:pharmacology*; D010421:Pentanoic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014631:Valerates / Q000494:pharmacology*
D006018:Glycols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones; D010421:Pentanoic Acids; D014631:Valerates