Recent Advances in the Development of Acetyl-CoA Carboxylase (ACC) Inhibitors for the Treatment of Metabolic Disease

Abstract

The development of acetyl-CoA carboxylase (ACC) inhibitors for the treatment of metabolic disease has been pursued by the pharmaceutical industry for some time. A number of recent disclosures describing potent ACC inhibitors have been reported by multiple research groups. Unlike many prior publications in this area, more recent publications contain a significant amount of in vivo efficacy data generated by long-term experiments in rodent models of metabolic disease. Additionally, one compound has been advanced to human clinical studies. The results from these studies should allow researchers to better gauge the potential utility of ACC inhibition for the treatment of human disease.

Modification of the Host Cell Lipid Metabolism Induced by Hypolipidemic Drugs Targeting the Acetyl Coenzyme A Carboxylase Impairs West Nile Virus Replication

“…Indeed, the clinical value of lipid-lowering agents such as the statins, which are cholesterol synthesis inhibitors broadly used against cardiovascular diseases, supports the feasibility of therapeutic interventions targeting the lipid metabolism (42). Consistently, hypolipidemic drugs targeting the ACC are being evaluated for the treatment of multiple human disorders from certain cancers to obesity and diabetes (20,21) and even viral infections (18,34,43). In addition, the results obtained with hypolipidemic agents (i.e., nordihydroguaiaretic acid) that target cellular factors other than ACC also support the feasibility of lipid-based antiviral approaches (17,44).…”

“…The enzyme preceding FASN in the fatty acid biosynthetic route is the acetyl-CoA carboxylase (ACC), which catalyzes the carboxylation of acetyl-CoA to malonyl-CoA. Due to its rate-limiting role in fatty acid synthesis, ACC is currently a target of increasing interest within the pharmacological industry (20,21). However, to our knowledge, the involvement of ACC in the replication of WNV, or other related flaviviruses, has not yet been evaluated.…”

Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats

“…In this regard, it is noteworthy that in 28-d rat and dog toxicology studies with ND-630, no adverse cardiac effects were observed at supratherapeutic doses (e.g., 428 times the FASyn inhibition ED 50 ). Finally, the robust efficacy of ND-630 relative to many of the CT domain-directed ACC inhibitors evaluated in chronic in vivo studies (28) has suggested that the distinct mode of action of ND-630 may offer specific efficacy advantages over CT domain inhibitors of similar affinity. For example, because ND-630 does not inhibit catalytic activity directly but instead inhibits enzyme activity by preventing dimerization, increased substrate and feedforward activator (citrate) levels that would occur postprandially and also could occur after ACC inhibition itself should have no effect on the inhibitory actions of ND-630, whereas they could attenuate the inhibitory actions of active site-directed CT domain inhibitors.…”

“…For example, because ND-630 does not inhibit catalytic activity directly but instead inhibits enzyme activity by preventing dimerization, increased substrate and feedforward activator (citrate) levels that would occur postprandially and also could occur after ACC inhibition itself should have no effect on the inhibitory actions of ND-630, whereas they could attenuate the inhibitory actions of active site-directed CT domain inhibitors. Similarly, the inhibitory actions of ND-630 would not be affected by the reduction in hepatic free fatty acids that occurs after chronic in vivo treatment and that would relieve feedback inhibition by fatty acyl-CoAs to attenuate the actions of CT domain inhibitors, possibly leading to the transient efficacy observed for many of these inhibitors (28). It is more likely, however, that the hydrophilic nature of the dimerization site with which ND-630 interacts facilitates the identification of highaffinity inhibitors that also possess favorable physiochemical and pharmacokinetic properties, whereas the hydrophobic nature of the binding sites with which CT domain inhibitors interact has made the identification of high-affinity inhibitors with favorable pharmaceutical properties more difficult (28).…”

“…A large number of isozyme-nonselective ACC inhibitors have been identified that interfere directly with ACC catalysis through interaction within the CT domain of the enzyme and have been shown to be potent in vitro and efficacious in vivo (1,9,19,(27)(28)(29)(30). Indeed, in early clinical trials one such inhibitor recently has been shown to reduce FASyn and to stimulate FAOxn after a single oral dose (29).…”