Acetyl-CoA carboxylase (ACC) is an enzyme which catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, and is considered as a key regulator of fatty acid metabolism. The inhibition of ACC is expected to reduce malonyl-CoA, resulting in decreased production of fatty acid, accelerated oxidation of fatty acid, and improvement of insulin sensitivity. Therefore, ACC is expected as an attractive target for the treatment of metabolic syndrome. There are two characterized isoforms of ACC known as ACC1 and ACC2. Genetic studies have demonstrated that the ACC1 knockout mice show embryonic lethality. In contrast, the ACC2 knockout mice are a normal and healthy phenotype, and have a higher fatty oxidation rate and lower body fat mass than wild-type mice. Therefore, ACC2 selective inhibition may offer a safe therapeutic potential for metabolic syndrome. In our research, novel ACC2 selective inhibitors were identified by the conversion of the alkyne unit of A-908292 to the olefin linker. Modification of the center and the left part on the lead compound 1 improved the inhibitory activity of ACC2 and CYP450 inhibition profile, and afforded a highly selective ACC2 inhibitor 2 which showed potent in vivo efficacy in C57BL/6 mice.

Discovery of a novel olefin derivative as a highly potent and selective acetyl-CoA carboxylase 2 inhibitor

2019 Spring National Meeting

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