Synthesis of arylnaphthalenyl derivatives: inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme a reductase.
Trans-tetrahydro-4-hydroxy-6-[1-aryl-7-naphthalenyl]-2H-pyran-2-ones of general structure 4 were prepared and tested for inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase in vitro. In contrast to previously described biphenyl lactones (2) containing an ethenyl linkage, linkage of the pyranone ring to the aryl moiety in these compounds is via a rigid aromatic ring system, which still allows free rotation of the aryl rings. The imposed conformational constraint is compatible with activity, since members of the series had activity in range 1-20 microM (IC50 values).
Mewshaw
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Medicinal Chemistry Section, Wyeth Laboratories, Inc., Philadelphia, PA 19101.
Hild
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Commons
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D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D005449:Fluorenes / Q000138:chemical synthesis / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D066298:In Vitro Techniques; D007783:Lactones / Q000138:chemical synthesis* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008148:Lovastatin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats
D001713:Biphenyl Compounds; D005449:Fluorenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones; D009281:Naphthalenes; C012258:mevastatin; D008148:Lovastatin