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Identification of novel mammalian squalene synthase inhibitors using a three-dimensional pharmacophore

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Publication details

JournalBioorganic and Medicinal Chemistry
DatePublished - Aug 2002
Issue number8
Volume10
Number of pages16
Pages (from-to)2641-2656
Original languageEnglish

Abstract

Squalene synthase (E.C. 2.5.1.21) catalyses the reductive dimerisation of farnesyl diphosphate in a [1-4] head to head fashion to form squalene, and is the first committed step in cholesterol biosynthesis. Specific inhibitors of squalene synthase would inhibit cholesterol formation and allow production of other important compounds derived front the cholesterol biosynthetic pathway, namely the ubiquinones (co-enzyme Q(10)), dolichol, and would also allow the isoprenylation process of ras by farnesyl-protein transferase. The construction of a hypothetical squalene synthase three-dimensional pharmacophore is presented. It serves as a template for the identification of several new potential classes of inhibitors. The synthesis, anti-microbial and mammalian pig liver squalene synthase activities of analogues based on the bicyclo[3.2.0]heptane and bicyclo[3.3.0]octane ring systems are reported. Analogues of the latter system Lire pro-drug type inhibitors and exhibit promising biological activity. (C) 2002 Published by Elsevier Science Ltd.

    Research areas

  • ZARAGOZIC ACID-C, STRUCTURE ELUCIDATION, CRYSTAL-STRUCTURE, POTENT INHIBITOR, ENZYME, PROSTAGLANDINS, KETENES, ROUTE, FORMS

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