C455

C455 is a potent, direct small molecule activator of 5’AMP-activated protein kinase (AMPK) that binds to the allosteric drug and metabolite (ADaM) site. Developed through a collaboration involving AstraZeneca and Gilead Sciences, it was investigated as a potential treatment for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). In preclinical mouse models (ob/ob mice on an Amylin-NASH diet), C455 demonstrated the ability to reduce liver steatosis, plasma ALT levels, and hepatic collagen gene expression. However, systemic activation of AMPK by C455 was associated with significant cardiac side effects, including increased heart weight (cardiac hypertrophy) and elevated cardiac glycogen storage, suggesting that systemic AMPK activation may have a limited therapeutic window for metabolic diseases.