3-Hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors. 7. Modification of the hexahydronaphthalene moiety of simvastatin: 5-oxygenated and 5-oxa derivatives.
Modification of the hexahydronaphthalene ring 5-position in simvastatin 2a via oxygenation and oxa replacement afforded two series of derivatives which were evaluated in vitro for inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and acutely in vivo for oral effectiveness as inhibitors of cholesterogenesis in the rat. Of the compounds selected for further biological evaluation, the 6 beta-methyl-5-oxa 10 and 5 alpha-hydroxy 16 derivatives of 3,4,4a,5-tetrahydro 2a, as well as, the 6 beta-epimer 14 of 16 proved orally active as hypocholesterolemic agents in cholestyramine-primed dogs. Subsequent acute oral metabolism studies in dogs demonstrated that compounds 14 and 16 evoke lower peak plasma drug activity and area-under-the-curve values than does compound 10 and led to the selection of 14 and 16 for toxicological evaluation.
Duggan
M E
ME
Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
Alberts
A W
AW
Bostedor
R
R
Chao
Y S
YS
Germershausen
J I
JI
Gilfillan
J L
JL
Halczenko
W
W
Hartman
G D
GD
Hunt
V
V
Imagire
J S
JS
D000085:Acetates / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D002784:Cholesterol / Q000096:biosynthesis; D004285:Dogs; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007700:Kinetics; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D010100:Oxygen; D051381:Rats; D019821:Simvastatin / Q000031:analogs & derivatives; D013329:Structure-Activity Relationship
C070477:6-(2-(8-(2,2-dimethylbutyryl)oxy)-2,6-dimethyl-5-hydroxy-1,2,3,4,4a,5,6,7,8,8a-decahydronaphthyl-1-ethyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; D000085:Acetates; D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D008148:Lovastatin; D019821:Simvastatin; D010100:Oxygen