title: The squalestatins: inhibitors of squalene synthase. Enzyme inhibitory activities and in vivo evaluation of C3-modified analogues.
abstract: Squalestatin analogues modified at C3 were prepared and evaluated for their ability to inhibit rat liver microsomal squalene synthase in vitro. While the 4,6-dimethyloctenoate ester group at C6 was maintained, a number of modifications to the C3 carboxylic acid were well tolerated. However, in the absence of the C6 ester group, similar modifications to the C3 carboxyl group caused loss of activity. Selected compounds were evaluated for their ability to inhibit cholesterol biosynthesis in vivo in rats 1 and 6 h postadministration. Analogues of squalestatin 1 (S1) modified at C3 were found to possess a shorter duration of effect in vivo which is reflected in their substantially reduced ability to lower serum cholesterol levels in marmosets. Significant cholesterol lowering (up to 62%) for the C3 hydroxymethyl analogue 1b was observed only when this compound was dosed three times a day for 3 days.
authors.affiliation: Department of Medicinal Chemistry, Glaxo Wellcome Research and Development, Medicines Research Center, Stevenage, United Kingdom.
authors.forename: P A
authors.initials: PA
authors.lastname: Procopiou
authors.forename: B
authors.initials: B
authors.lastname: Cox
authors.forename: B E
authors.initials: BE
authors.lastname: Kirk
authors.forename: M G
authors.initials: MG
authors.lastname: Lester
authors.forename: A D
authors.initials: AD
authors.lastname: McCarthy
authors.forename: M
authors.initials: M
authors.lastname: Sareen
authors.forename: P J
authors.initials: PJ
authors.lastname: Sharratt
authors.forename: M A
authors.initials: MA
authors.lastname: Snowden
authors.forename: S J
authors.initials: SJ
authors.lastname: Spooner
authors.forename: N S
authors.initials: NS
authors.lastname: Watson
authors.forename: J
authors.initials: J
authors.lastname: Widdowson
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D002144:Callithrix / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004952:Esters / Q000138:chemical synthesis / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D051381:Rats; D014233:Tricarboxylic Acids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D000924:Anticholesteremic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D004952:Esters; D014233:Tricarboxylic Acids; C075117:squalestatin 1; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase