Discovery of 3,5-Dimethylpyridin-4(1H)-one Derivatives as Activators of AMP-Activated Protein Kinase (AMPK)

摘要

Novel 3,5-dimethylpyridin-4(1 H )-one scaffold compounds were synthesized and evaluated as AMP-activated protein kinase (AMPK) activators. Unlike direct AMPK activators, this series of compounds showed selective cell growth inhibitory activity against human breast cancer cell lines. By optimizing the lead compound ( 4a ) from our library, 2-[({1′-[(4-fluorophenyl)methyl]-2-methyl-1′,2′,3′,6′-tetrahydro[3,4′-bipyridin]-6-yl}oxy)methyl]-3,5-dimethylpyridin-4(1 H )-one ( 25 ) was found to have potent AMPK activating activity. Compound 25 also showed good aqueous solubility while maintaining the unique selectivity in cell growth inhibitory activity.