ATP-Citrate lyase as a target for hypolipidemic intervention. 2. Synthesis and evaluation of (3R,5S)-omega-substituted-3-carboxy-3, 5-dihydroxyalkanoic acids and their gamma-lactone prodrugs as inhibitors of the enzyme in vitro and in vivo

A D Gribble; R J Ife; A Shaw; D McNair; C E Novelli; S Bakewell; V P Shah; R E Dolle; P H Groot; N Pearce; J Yates; D Tew; H Boyd; S Ashman; D S Eggleston; R C Haltiwanger; G Okafo

doi:10.1021/jm980091z

ATP-Citrate lyase as a target for hypolipidemic intervention. 2. Synthesis and evaluation of (3R,5S)-omega-substituted-3-carboxy-3, 5-dihydroxyalkanoic acids and their gamma-lactone prodrugs as inhibitors of the enzyme in vitro and in vivo

J Med Chem. 1998 Sep 10;41(19):3582-95. doi: 10.1021/jm980091z.

Authors

A D Gribble¹, R J Ife, A Shaw, D McNair, C E Novelli, S Bakewell, V P Shah, R E Dolle, P H Groot, N Pearce, J Yates, D Tew, H Boyd, S Ashman, D S Eggleston, R C Haltiwanger, G Okafo

Affiliation

¹ Departments of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals Ltd, New Frontiers Science Park (North), Third Avenue, Harlow, Essex CM19 5AW, UK.

PMID: 9733484
DOI: 10.1021/jm980091z

Abstract

A series of (3R,5S)-omega-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 Ki's in the 200-1000 nM range. As the corresponding thermodynamically favored gamma-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.

MeSH terms

ATP Citrate (pro-S)-Lyase / antagonists & inhibitors*
Administration, Oral
Animals
Anticholesteremic Agents / administration & dosage
Anticholesteremic Agents / chemical synthesis
Anticholesteremic Agents / chemistry
Anticholesteremic Agents / pharmacology
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
Humans
Hypolipidemic Agents / administration & dosage
Hypolipidemic Agents / chemical synthesis*
Hypolipidemic Agents / chemistry
Hypolipidemic Agents / pharmacology
Lipids / biosynthesis
Lipoproteins, VLDL / blood
Prodrugs / administration & dosage
Prodrugs / chemical synthesis*
Prodrugs / chemistry
Prodrugs / pharmacology
Rats
Recombinant Proteins / antagonists & inhibitors
Structure-Activity Relationship
Triglycerides / blood

Substances

3-(carboxymethyl)-5-(6-(2,4-dichlorophenyl)hexyl)-3-hydroxytetrahydrofuran-2-one
3-carboxy-11-(2,4-dichlorophenyl)-3,5-dihydroxyundecanoic acid
Anticholesteremic Agents
Enzyme Inhibitors
Fatty Acids
Furans
Hypolipidemic Agents
Lipids
Lipoproteins, VLDL
Prodrugs
Recombinant Proteins
Triglycerides
Cholesterol
ATP Citrate (pro-S)-Lyase