ATP-Citrate Lyase as a Target for Hypolipidemic Intervention. 2. Synthesis and Evaluation of (3R,5S)-ω-Substituted-3-carboxy-3,5-dihydroxyalkanoic Acids and Their γ-Lactone Prodrugs as Inhibitors of the Enzyme in Vitro and in Vivo

• Published in: Journal of medicinal chemistry 1998-09, Vol.41 (19), p.3582-3595
• Main Authors: Gribble, Andrew D, Ife, Robert J, Shaw, Antony, McNair, David, Novelli, Christine E, Bakewell, Susan, Shah, Virendra P, Dolle, Roland E, Groot, Pieter H, Pearce, Nigel, Yates, John, Tew, David, Boyd, Helen, Ashman, Stephen, Eggleston, Drake S, Haltiwanger, R. Curtis, Okafo, George
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anticholesteremic Agents - administration & dosage; Anticholesteremic Agents - chemical synthesis; Anticholesteremic Agents - chemistry; Anticholesteremic Agents - pharmacology; ATP Citrate (pro-S)-Lyase - antagonists & inhibitors; Biological and medical sciences; Cell Line; Cholesterol - blood; Dogs; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Fatty Acids - chemistry; Fatty Acids - pharmacology; Furans - administration & dosage; Furans - chemical synthesis; Furans - chemistry; Furans - pharmacology; General and cellular metabolism. Vitamins; Humans; Hypolipidemic Agents - administration & dosage; Hypolipidemic Agents - chemical synthesis; Hypolipidemic Agents - chemistry; Hypolipidemic Agents - pharmacology; Lipids - biosynthesis; Lipoproteins, VLDL - blood; Medical sciences; Pharmacology. Drug treatments; Prodrugs - administration & dosage; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Rats; Recombinant Proteins - antagonists & inhibitors; Structure-Activity Relationship; Triglycerides - blood
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980091z

A series of (3R*,5S*)-ω-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 K i's in the 200−1000 nM range. As the corresponding thermodynamically favored γ-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.