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

A series of (3<i>R</i>*,5<i>S</i>*)-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 <i>K</i><sub>i</sub>'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 <b>77</b>, 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.