ATP-CITRATE LYASE AS A TARGET FOR HYPOLIPIDEMIC INTERVENTION - 2 - SYNTHESIS AND EVALUATION OF -OMEGA-SUBSTITUTED-3-CARBOXY-3,5-DIHYDROXYALKANOIC ACIDS AND THEIR GAMMA-LACTONE PRODRUGS AS INHIBITORS OF THE ENZYME IN-VITRO AND IN-VIVO

series of -omega-substituted-3-carboxy-3,5-dihydroxyalkanoic acids hav e been synthesized and evaluated as inhibitors of the recombinant huma n form of ATP-citrate lyase. The best of these have K-i's in the 200-1 000 nM range. As the corresponding thermodynamically favored gamma-lac tone prodrugs, a number of compounds are able to inhibit cholesterol a nd fatty acid synthesis in HepG2 cells and reduce plasma triglyceride levels in vivo. The best of these, compound 77, is able to induce clea r hypocholesterolemic and hypotriglyceridaemic responses when administ ered 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 c ombined hypocholesterolemic and hypotriglyceridemic activities.