title: 3-Hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors. 7. Modification of the hexahydronaphthalene moiety of simvastatin: 5-oxygenated and 5-oxa derivatives.
abstract: 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.
authors.affiliation: Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: M E
authors.initials: ME
authors.lastname: Duggan
authors.forename: A W
authors.initials: AW
authors.lastname: Alberts
authors.forename: R
authors.initials: R
authors.lastname: Bostedor
authors.forename: Y S
authors.initials: YS
authors.lastname: Chao
authors.forename: J I
authors.initials: JI
authors.lastname: Germershausen
authors.forename: J L
authors.initials: JL
authors.lastname: Gilfillan
authors.forename: W
authors.initials: W
authors.lastname: Halczenko
authors.forename: G D
authors.initials: GD
authors.lastname: Hartman
authors.forename: V
authors.initials: V
authors.lastname: Hunt
authors.forename: J S
authors.initials: JS
authors.lastname: Imagire
mesh_terms: 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
chemical_list: 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