Identification and Synthesis of Novel Inhibitors of Acetyl-CoA Carboxylase with in Vitro and in Vivo Efficacy on Fat Oxidation

Abstract

Acetyl CoA carboxylase isoforms 1 and 2 (ACC1/2) are key enzymes of fat utilization and their inhibition is considered to improve aspects of the metabolic syndrome. To identify pharmacological inhibitors of ACC1/2, a high throughput screen was performed which resulted in the identification of the lead compound 3 ( Gargazanli , G. ; Lardenois , P. ; Frost , J. ; George , P. Patent WO9855474 A1, 1998 ) as a moderate selective ACC2 inhibitor. Optimization of 3 led to 4m ( Zoller , G. ; Schmoll , D. ; Mueller , M. ; Haschke , G. ; Focken , I. Patent WO2010003624 A2, 2010 ) as a submicromolar dual ACC1/2 inhibitor of the rat and human isoforms. 4m possessed favorable pharmacokinetic parameters. This compound stimulated fat oxidation in vivo and reduced plasma triglyceride levels in a rodent model after subchronic administration. 4m is a suitable tool compound for the elucidation of the pharmacological potential of ACC1/2 inhibition.

Inhibition of acetyl-CoA carboxylase 2 enhances skeletal muscle fatty acid oxidation and improves whole-body glucose homeostasis in db/db mice

“…The ACC non-selective inhibitor 4m stimulated fat oxidation as shown by lowering of the respiratory quotient and reducing plasma triacylglycerol levels in a rodent model of dyslipidaemia [18]. Soraphen, another non-selective inhibitor of ACC, was demonstrated to improve peripheral insulin sensitivity in high-fat-fed mice [38].…”

“…Accordingly, genetic deletion of Acc2 (also known as Acacb) has been reported to result in reduced muscle malonyl-CoA levels and enhanced fatty acid oxidation [14,15], though this has not been consistently demonstrated [16]. However, pharmacological inhibition using isoform-non-selective ACC inhibitors stimulated fat oxidation and reduced plasma triacylglycerol levels in a rodent model of dyslipidaemia [17,18]; an unresolved question is whether specific inhibition of ACC2 is sufficient to achieve a comparable effect.…”

Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle

“…Both fat and carbohydrate oxidation were simultaneously increased in ACC2 −/− mice, which was curiously credited as the impetus for increased total body energy expenditure without consideration of potential changes in energy demand (Choi et al, 2007). Nevertheless, based on the reduced fat mass and improved glucose metabolism evident in these mice, ACC2 became a prime target for pharmaceutical development (Keil et al, 2010). Intriguingly however, two other groups have recently generated whole body- and muscle-specific ACC2 knockout models and found no effect of the gene deletion on body weight, food intake, body composition and susceptibility to diet-induced obesity and glucose intolerance (Hoehn et al, 2010; Olson et al, 2010).…”

Network-based assessment of the selectivity of metabolic drug targets in Plasmodium falciparum with respect to human liver metabolism

“…The reduced fitness approach correctly predicted that the enzymatic inhibition of acetyl-CoA carboxylase causes an importing of plasma triglycerides and this phenomenon has been experimentally demonstrated in vitro [28]. Acetyl-CoA carboxylase is the rate-limiting step of the fatty acid anabolism and it is essential for human breast cancer cells [29].…”