Discovery of potent and liver-selective stearoyl-CoA desaturase (SCD) inhibitors in an acyclic linker series

The synthesis of potent and liver-selective SCD inhibitors containing an acyclic chain as the linker joining the key heterocyclic core and terminal aromatic ring is described. The structure–activity relationships, the optimization to solve metabolic issues and the in vivo biological activity of this new series of liver-targeting SCD inhibitors are reported. Elevated levels of stearoyl-CoA desaturase (SCD) activity have been implicated in metabolic disorders such as obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed inhibitors, our research efforts have been focused on the search for new liver-targeting compounds. This work has led to the discovery of novel, potent and liver-selective acyclic linker SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.