title: The squalestatins: decarboxy and 4-deoxy analogues as potent squalene synthase inhibitors.
abstract: Squalestatins without either the hydroxy group at C-4 or the carboxylic acid at C-3 or C-4 were prepared and evaluated for their ability to inhibit rat liver microsomal squalene synthase (SQS) in vitro. These modifications were well tolerated for compounds with the 4,6-dimethyloctenoate ester at C-6 (S1 series). However in analogues without the C-6 ester (H1 series), removal of the C-4 hydroxy group gave compounds with reduced potency, whereas decarboxylation at C-3 resulted in a dramatic loss of SQS inhibitory activity. In comparison with S1 1, C-4 deoxyS1 3 and C-3 decarboxyS1 10 have shorter in vivo durations of action on the inhibition of hepatic cholesterol biosynthesis in rats. C-4 deoxyS1 3 retains good serum cholesterol-lowering ability in marmosets, while C-3 decarboxyS1 10 showed only a marginal effect even at high dose.
authors.affiliation: Glaxo Wellcome Research & Development, Medicines Research Centre, Stevenage, Herfordshire, UK.
authors.forename: C
authors.initials: C
authors.lastname: Chan
authors.forename: D
authors.initials: D
authors.lastname: Andreotti
authors.forename: B
authors.initials: B
authors.lastname: Cox
authors.forename: B W
authors.initials: BW
authors.lastname: Dymock
authors.forename: J L
authors.initials: JL
authors.lastname: Hutson
authors.forename: S E
authors.initials: SE
authors.lastname: Keeling
authors.forename: A D
authors.initials: AD
authors.lastname: McCarthy
authors.forename: P A
authors.initials: PA
authors.lastname: Procopiou
authors.forename: B C
authors.initials: BC
authors.lastname: Ross
authors.forename: M
authors.initials: M
authors.lastname: Sareen
authors.forename: J J
authors.initials: JJ
authors.lastname: Scicinski
authors.forename: P J
authors.initials: PJ
authors.lastname: Sharratt
authors.forename: M A
authors.initials: MA
authors.lastname: Snowden
authors.forename: N S
authors.initials: NS
authors.lastname: Watson
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002144:Callithrix; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D013185:Squalene / Q000378:metabolism; D013329:Structure-Activity Relationship; D014233:Tricarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000924:Anticholesteremic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D014233:Tricarboxylic Acids; C075117:squalestatin 1; D013185:Squalene; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase