Discovery of the 2,3-Dihydrobenzopyrane-4-one as a Potent FTO Inhibitor against Obesity-Related Metabolic Diseases

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-03-28 DOI:10.1021/acs.jmedchem.4c03124

Duo Ma, Xianan Liu, Xingxing Zhang, Yaling Hong, Yumeng Wang, Famin Zhang, Leran Du, Junjie Zhao, Quan Wang, Cui Chang, Wenhu Liu, Yan Lou, Xinhua Liu

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Abstract

The involvement of the fat mass and obesity-associated gene (FTO) in the development and advancement of metabolic disorders is widely recognized. However, the existing FTO inhibitor entacapone has been limited in clinical application due to its low potency and short plasma elimination half-life. Here, through drug library screening and in depth structure–activity relationship analysis, title compound 40, eriodictyol was identified as a potent FTO inhibitor, and showed good binding to FTO by surface plasmon resonance (SPR) and Microscale thermophoresis (MST) detection. The residues Arg96, Tyr108, Ser229, Asp233, and Glu234 of FTO are essential for binding. Meanwhile, eriodictyol attenuated obesity-related metabolic diseases by enhancing glucose metabolism pathways via the FTO-FOXO1-G6PC/PCK1 axis and increasing adipose tissue heat production for weight loss via the FTO-FOXO1-Ucp1 axis in vivo. Surprisingly, eriodictyol showed good pharmacokinetic properties and no obvious toxicity. These results could provide the reference for design of new FTO inhibitors against obesity-related metabolic diseases.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.