Design, synthesis, and structure–activity relationships of novel spiro-piperidines as acetyl-CoA carboxylase inhibitors

Abstract Spiro-lactone ( S )- 1 is a potent acetyl-CoA carboxylase (ACC) inhibitor and was found to be metabolically liable in human hepatic microsomes. To remove one of the risk factors in human study by improving the metabolic stability, we focused on modifying the spiro-lactone ring and the benzothiophene portion of the molecule. Spiro-imide derivative 8c containing a 6-methylthieno[2,3- b ]pyridine core exhibited potent ACC inhibitory activity and favorable pharmacokinetic profiles in rats.