Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals.
Inhibition of acetyl-CoA carboxylase (ACC), with its resultant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation, has the potential to favorably affect the multitude of cardiovascular risk factors associated with the metabolic syndrome. To achieve maximal effectiveness, an ACC inhibitor should inhibit both the lipogenic tissue isozyme (ACC1) and the oxidative tissue isozyme (ACC2). Herein, we describe the biochemical and acute physiological properties of CP-610431, an isozyme-nonselective ACC inhibitor identified through high throughput inhibition screening, and CP-640186, an analog with improved metabolic stability. CP-610431 inhibited ACC1 and ACC2 with IC50s of approximately 50 nm. Inhibition was reversible, uncompetitive with respect to ATP, and non-competitive with respect to bicarbonate, acetyl-CoA, and citrate, indicating interaction with the enzymatic carboxyl transfer reaction. CP-610431 also inhibited fatty acid synthesis, triglyceride (TG) synthesis, TG secretion, and apolipoprotein B secretion in HepG2 cells (ACC1) with EC50s of 1.6, 1.8, 3.0, and 5.7 microm, without affecting either cholesterol synthesis or apolipoprotein CIII secretion. CP-640186, also inhibited both isozymes with IC50sof approximately 55 nm but was 2-3 times more potent than CP-610431 in inhibiting HepG2 cell fatty acid and TG synthesis. CP-640186 also stimulated fatty acid oxidation in C2C12 cells (ACC2) and in rat epitrochlearis muscle strips with EC50s of 57 nm and 1.3 microm. In rats, CP-640186 lowered hepatic, soleus muscle, quadriceps muscle, and cardiac muscle malonyl-CoA with ED50s of 55, 6, 15, and 8 mg/kg. Consequently, CP-640186 inhibited fatty acid synthesis in rats, CD1 mice, and ob/ob mice with ED50s of 13, 11, and 4 mg/kg, and stimulated rat whole body fatty acid oxidation with an ED50 of approximately 30 mg/kg. Taken together, These observations indicate that isozyme-nonselective ACC inhibition has the potential to favorably affect risk factors associated with the metabolic syndrome.
Harwood
H James
HJ
Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc., Groton, Connecticut 06340, USA. h_james_harwood@groton.pfizer.com
Petras
Stephen F
SF
Shelly
Lorraine D
LD
Zaccaro
Lawrence M
LM
Perry
David A
DA
Makowski
Michael R
MR
Hargrove
Diane M
DM
Martin
Kelly A
KA
Tracey
W Ross
WR
Chapman
Justin G
JG
Magee
William P
WP
Dalvie
Deepak K
DK
Soliman
Victor F
VF
Martin
William H
WH
Mularski
Christian J
CJ
Eisenbeis
Shane A
SA
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008099:Liver / Q000378:metabolism; D008297:Male; D008316:Malonyl Coenzyme A / Q000032:analysis*; D051379:Mice; D008809:Mice, Inbred C3H; D018482:Muscle, Skeletal / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000096:biosynthesis
D004791:Enzyme Inhibitors; D005227:Fatty Acids; D007527:Isoenzymes; D014280:Triglycerides; D008316:Malonyl Coenzyme A; D000103:Acetyl-CoA Carboxylase