A novel pyridine-2-one AMPK inhibitor: discovery, mechanism, and in vivo evaluation in a hypoxic pulmonary arterial hypertension rat model

AMP-activated protein kinase (AMPK), a heterotrimeric serine-threonine kinase, has been identified as a promising target for regulating vascular remodeling in pulmonary arterial hypertension (PAH) due to its capacity to promote proliferation, autophagy, and anti-apoptosis in pulmonary artery smooth muscle cells (PASMCs). However, research into AMPK inhibitors is very limited. Herein, a virtual screening strategy was employed to identify CHEMBLE3780091 as a lead compound for a series of novel AMPK inhibitors by exploring the structure-activity relationship around a specific pyridine-2-one scaffold. Subsequently, the most promising 13a was observed to exhibit excellent AMPK inhibitory activity and favorable anti-proliferative activity against PASMCs through the inhibition of the AMPK signaling pathway in vitro. Moreover, compound 13a significantly reduced right ventricular systolic pressure, attenuated vascular remodeling, and improved right heart function in hypoxia-induced PAH rats in vivo. In conclusion, this study provides a novel and potential lead compound for the study of AMPK inhibitors and a new direction for the development of PAH drugs that focus on improving vascular remodeling.