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

Wenhua Tan; Yu Wang; Mengqi Li; Congke Zhao; Yuanbo Hu; Ruizhe Gao; Zhuo Chen; Liqing Hu; Qianbin Li

doi:10.1016/j.ejmech.2025.117266

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

Eur J Med Chem. 2025 Jan 12:286:117266. doi: 10.1016/j.ejmech.2025.117266. Online ahead of print.

Authors

Wenhua Tan¹, Yu Wang¹, Mengqi Li¹, Congke Zhao¹, Yuanbo Hu¹, Ruizhe Gao², Zhuo Chen¹, Liqing Hu³, Qianbin Li⁴

Affiliations

¹ Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Changsha, 410013, Hunan, China.
² Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, 410013, Hunan, China.
³ Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, 410013, Hunan, China. Electronic address: [email protected].
⁴ Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Changsha, 410013, Hunan, China. Electronic address: [email protected].

PMID: 39826489
DOI: 10.1016/j.ejmech.2025.117266

Abstract

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 CHEMBL3780091 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.

Keywords: AMP-Activated protein kinase; Pulmonary arterial hypertension; Structure optimization; Vascular remodeling; Virtual screening.