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 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.
Gribble
A D
AD
Departments of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals Ltd, New Frontiers Science Park (North), Third Avenue, Harlow, Essex CM19 5AW, UK.
Ife
R J
RJ
Shaw
A
A
McNair
D
D
Novelli
C E
CE
Bakewell
S
S
Shah
V P
VP
Dolle
R E
RE
Groot
P H
PH
Pearce
N
N
Yates
J
J
Tew
D
D
Boyd
H
H
Ashman
S
S
Eggleston
D S
DS
Haltiwanger
R C
RC
Okafo
G
G
D001275:ATP Citrate (pro-S)-Lyase / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002784:Cholesterol / Q000097:blood; D004285:Dogs; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005227:Fatty Acids / Q000737:chemistry* / Q000494:pharmacology; D005663:Furans / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008055:Lipids / Q000096:biosynthesis; D008079:Lipoproteins, VLDL / Q000097:blood; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood
C114594:3-(carboxymethyl)-5-(6-(2,4-dichlorophenyl)hexyl)-3-hydroxytetrahydrofuran-2-one; C114593:3-carboxy-11-(2,4-dichlorophenyl)-3,5-dihydroxyundecanoic acid; D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D005663:Furans; D000960:Hypolipidemic Agents; D008055:Lipids; D008079:Lipoproteins, VLDL; D011355:Prodrugs; D011994:Recombinant Proteins; D014280:Triglycerides; D002784:Cholesterol; D001275:ATP Citrate (pro-S)-Lyase