Identification of AdipoRon analogues as novel activators of AMPK for the treatment of type 2 diabetes†

Abstract

The activation of AMPK has emerged as a promising therapeutic approach for the treatment of metabolic diseases. AdipoRon, an agonist of the adiponectin receptor, has been identified as a compound capable of activating AMPK via the adiponectin receptor. To identify novel AdipoRon analogues with AMPK activation potential, a total of 17 analogues were designed, synthesized, and subjected to biological evaluation. Among these analogues, X-12 was discovered to exhibit potent activation of AMPK. In experimental studies, X-12 demonstrated dose-dependent improvements in glucose tolerance in normal mice. Furthermore, it significantly reduced fasting blood glucose levels and ameliorated insulin resistance in db/db diabetic mice. These findings highlight the therapeutic potential of X-12 as a novel class of AMPK activators for the treatment of metabolic diseases.