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

Andrew D. Gribble, Robert J. Ife, Antony Shaw, David McNair, Christine E. Novelli, Susan Bakewell, Virendra P. Shah, Roland E. Dolle, Pieter H. Groot, Nigel Pearce, John Yates, David Tew, Helen Boyd, Stephen Ashman, Drake S. Eggleston, R. Curtis Haltiwanger, George Okafo

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)3582-3595
Number of pages14
JournalJournal of Medicinal Chemistry
Volume41
Issue number19
DOIs
StatePublished - Sep 10 1998

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this