title: ATP-citrate lyase as a target for hypolipidemic intervention. Design and synthesis of 2-substituted butanedioic acids as novel, potent inhibitors of the enzyme.
abstract: ATP-citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. Inhibitors of the enzyme represent a potentially novel class of hypolipidemic agent, which are anticipated to have combined hypocholesterolemic and hypotriglyceridemic properties. A series of 2-substituted butanedioic acids have been designed and synthesized as inhibitors of the enzyme. The best compounds, 58, 68, 71, 74 have reversible Ki's in the 1-3 microM range against the isolated rat enzyme. As representative of this compound class, 58, has been shown to exert its inhibitory action through a mainly competitive mechanism with respect to citrate and a noncompetitive one with respect to CoA. None of the inhibitors were able to inhibit cholesterol and/or fatty acid synthesis in HepG2 cells. This has been attributed to the adverse physicochemical properties of the molecules leading to a lack of cell penetration. Despite this, a lead structural class of compound has been identified with the potential for modification into potent, cell-penetrant, and efficacious inhibitors of ATP-citrate lyase.
authors.affiliation: Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals Ltd, Welwyn, Hertfordshire, U.K.
authors.forename: A D
authors.initials: AD
authors.lastname: Gribble
authors.forename: R E
authors.initials: RE
authors.lastname: Dolle
authors.forename: A
authors.initials: A
authors.lastname: Shaw
authors.forename: D
authors.initials: D
authors.lastname: McNair
authors.forename: R
authors.initials: R
authors.lastname: Novelli
authors.forename: C E
authors.initials: CE
authors.lastname: Novelli
authors.forename: B P
authors.initials: BP
authors.lastname: Slingsby
authors.forename: V P
authors.initials: VP
authors.lastname: Shah
authors.forename: D
authors.initials: D
authors.lastname: Tew
authors.forename: B A
authors.initials: BA
authors.lastname: Saxty
authors.forename: M
authors.initials: M
authors.lastname: Allen
authors.forename: P H
authors.initials: PH
authors.lastname: Groot
authors.forename: N
authors.initials: N
authors.lastname: Pearce
authors.forename: J
authors.initials: J
authors.lastname: Yates
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000037:antagonists & inhibitors*; D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D051381:Rats; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D001275:ATP Citrate (pro-S)-Lyase