title: Identification of novel mammalian squalene synthase inhibitors using a three-dimensional pharmacophore.
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 from 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 are pro-drug type inhibitors and exhibit promising biological activity.
authors.affiliation: Department of Chemistry and Materials, John Dalton Building, The Manchester Metropolitan University, Chester Street, Manchester M20 5GD, UK. ijsf1@york.ac.uk
authors.forename: Ian J S
authors.initials: IJ
authors.lastname: Fairlamb
authors.forename: Julia M
authors.initials: JM
authors.lastname: Dickinson
authors.forename: Rachael
authors.initials: R
authors.lastname: O'Connor
authors.forename: Seamus
authors.initials: S
authors.lastname: Higson
authors.forename: Lynsey
authors.initials: L
authors.lastname: Grieveson
authors.forename: Veronica
authors.initials: V
authors.lastname: Marin
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D005658:Fungi / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000166:cytology / Q000201:enzymology; D008322:Mammals; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D013186:Farnesyl-Diphosphate Farnesyltransferase