Yue Wu, Zewei Zhang, Haiping Cai, Weiqing Zhang, Linjian Zhang, Zhihong Li, Le Yang, Yafen Chen, Thomas P. Corner, Zhe Song, Jie Yue, Fulai Yang, Xiang Li, Christopher J. Schofield, Xiaojin Zhang
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引用次数: 0
Abstract
Genetic loss of the 2-oxoglutarate oxygenase factor inhibiting hypoxia-inducible factor (FIH) enhances both glycolysis and aerobic metabolism. FIH is thus a potential target for adiposity control and improving hepatic steatosis. We describe development of a series of novel, potent, and selective FIH inhibitors that occupy both the FIH catalytic site and a recently defined tyrosine conformational-flip pocket. ZG-2305, with a Ki of 79.6 nM for FIH, manifests 38-fold selectivity over the hypoxia-inducible factor (HIF) prolyl hydroxylase PHD2. Oral administration of ZG-2305 in the western-diet induced obesity mouse model results in improved lipid accumulation and recovery from abnormal body weight/hepatic steatosis. Amelioration of nonalcoholic steatohepatitis (NASH) related pathological phenotypes in the HF-CDAA-diet induced NASH mouse model was observed. Preliminary preclinical studies indicate ZG-2305 has good pharmacokinetic properties and an acceptable safety profile. The results imply ZG-2305 is a promising candidate for treatment of obesity and fatty liver disease.
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.