ATP-citrate lyase as a target for hypolipidemic intervention. Design and synthesis of 2-substituted butanedioic acids as novel, potent inhibitors of the enzyme

Andrew D. Gribble, Roland E. Dolle, Antony Shaw, David McNair, Riccardo Novelli, Christine E. Novelli, Brian P. Slingsby, Virendra P. Shah, David Tew, Barbara A. Saxty, Mark Allen, Pieter H. Groot, Nigel Pearce, John Yates

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32 Scopus citations

Abstract

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 K(i)'s in the 1-3 μM 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.

Original languageEnglish
Pages (from-to)3569-3584
Number of pages16
JournalJournal of Medicinal Chemistry
Volume39
Issue number18
DOIs
StatePublished - 1996

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