ABSTRACT
A series of (3R,5S)-omega-substituted-3-carboxy-3, 5-dihydroxyalkanoic acids have been synthesized and evaluated as inhibitors of the recombinant human form of ATP-citrate lyase. The best of these have Ki's in the 200-1000 nM range. As the corresponding thermodynamically favored gamma-lactone prodrugs, a number of compounds are able to inhibit cholesterol and fatty acid synthesis in HepG2 cells and reduce plasma triglyceride levels in vivo. The best of these, compound 77, is able to induce clear hypocholesterolemic and hypotriglyceridaemic responses when administered orally to rat and dog. These results provide evidence to support the hypothesis that compounds which inhibit ATP-citrate lyase have the potential to be a novel class of hypolipidemic agent, which possess combined hypocholesterolemic and hypotriglyceridemic activities.
Subject(s)
ATP Citrate (pro-S)-Lyase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Fatty Acids/chemistry , Furans/chemical synthesis , Hypolipidemic Agents/chemical synthesis , Prodrugs/chemical synthesis , Administration, Oral , Animals , Anticholesteremic Agents/administration & dosage , Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Cell Line , Cholesterol/blood , Dogs , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Fatty Acids/pharmacology , Furans/administration & dosage , Furans/chemistry , Furans/pharmacology , Humans , Hypolipidemic Agents/administration & dosage , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacology , Lipids/biosynthesis , Lipoproteins, VLDL/blood , Prodrugs/administration & dosage , Prodrugs/chemistry , Prodrugs/pharmacology , Rats , Recombinant Proteins/antagonists & inhibitors , Structure-Activity Relationship , Triglycerides/bloodABSTRACT
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.
