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.