title: Synthesis and biological evaluation of dihydroeptastatin, a novel inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase.
abstract: The total synthesis of the novel hydroxylated HMG-CoA reductase inhibitor dihydroeptastatin (7) is described. The key C-3 hydroxyl group is introduced via a Baeyer-Villiger reaction on the methyl ketone 17 which is obtained in three high-yielding steps from the known tricyclic lactone 12. In an isolated enzyme assay dihydroeptastatin had a similar IC50 to mevinolin but in cellular assays using Hep G2 and HES 9 cell lines, dihydroeptastatin was much less potent. No selectivity between the two cell lines was observed.
authors.affiliation: Department of Medicinal Chemistry, British Bio-technology Limited, Cowley, Oxford, U.K.
authors.forename: E A
authors.initials: EA
authors.lastname: Bone
authors.forename: A H
authors.initials: AH
authors.lastname: Davidson
authors.forename: C N
authors.initials: CN
authors.lastname: Lewis
authors.forename: R S
authors.initials: RS
authors.lastname: Todd
mesh_terms: D000818:Animals; D006903:Hydroxymethylglutaryl CoA Reductases / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017035:Pravastatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C076822:dihydroeptastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D017035:Pravastatin