ATP-citrate lyase as a target for hypolipidemic intervention. Design and synthesis of 2-substituted butanedioic acids as novel, potent inhibitors of the enzyme.
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.
Gribble
A D
AD
Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals Ltd, Welwyn, Hertfordshire, U.K.
Dolle
R E
RE
Shaw
A
A
McNair
D
D
Novelli
R
R
Novelli
C E
CE
Slingsby
B P
BP
Shah
V P
VP
Tew
D
D
Saxty
B A
BA
Allen
M
M
Groot
P H
PH
Pearce
N
N
Yates
J
J
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
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D001275:ATP Citrate (pro-S)-Lyase