3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 9. The synthesis and biological evaluation of novel simvastatin analogs.
Substitution of hydroxy and hydroxyalkyl functionality at C-7 of the hexahydronaphthalene nucleus of simvastatin has provided novel analogs. The synthetic strategy employed epoxidation or Lewis acid-catalyzed aldol reaction of the 8-keto silyl enol ether as a key reactive intermediate. These analogs were evaluated as potential hypocholesterolemic agents via initial determination of their ability to inhibit HMG-CoA reductase in vitro. Oral activity of these compounds was determined in an acute rat model and a three-week study in cholestyramine-primed dogs. Compounds were identified that possessed in vitro and in vivo activity comparable to that of simvastatin.
Hartman
G D
GD
Merck Research Laboratories, West Point, Pennsylvania 19486.
Halczenko
W
W
Duggan
M E
ME
Imagire
J S
JS
Smith
R L
RL
Pitzenberger
S M
SM
Fitzpatrick
S L
SL
Alberts
A W
AW
Bostedor
R
R
Chao
Y S
YS
D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006937:Hypercholesterolemia / Q000188:drug therapy; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D009682:Magnetic Resonance Spectroscopy; D051381:Rats; D019821:Simvastatin; D013329:Structure-Activity Relationship
D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D019821:Simvastatin