溴邻苯二酚-查尔酮衍生物对 PTP1B 的异位抑制作用

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL European Journal of Medicinal Chemistry Pub Date : 2024-11-13 DOI:10.1016/j.ejmech.2024.117053

Chenxia Gao, Wenpeng Hu, Feng Xu, Yuxi Lin, Jiashu Chen, Dayong Shi, Pan Xing, Jiqiang Zhu, Xiangqian Li

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引用次数: 0

摘要

开发异构抑制剂可能是发现针对 PTP1B 的降糖药物的可行策略。异构抑制剂占据的 BB 位点是一个疏水口袋，它限制了处于开放构象的 WPD 环，从而阻止了生理上的去磷酸化反应。针对 BB 位点，研究人员设计并合成了 60 种溴邻苯二酚-查尔酮衍生物，作为 PTP1B 的异构抑制剂，以防治糖尿病。最有效的化合物 LXQ-87（C8）对 PTP1B 具有非竞争性抑制作用，IC50 值为 1.061±0.202 μM。口服 LXQ-87 可降低 BKS db/db T2DM 小鼠的空腹血糖水平，改善糖耐量和血脂异常。LXQ-87 通过直接与细胞内的 PTP1B 结合，缓解了胰岛素抵抗，促进了细胞的葡萄糖摄取。

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Allosteric inhibition of PTP1B by bromocatechol-chalcone derivatives

Development of allosteric inhibitors may be a viable strategy to discover hypoglycemic drugs targeting PTP1B. Allosteric inhibitors occupying the BB site that is a hydrophobic pocket restrict the WPD loop in an open conformation, preventing the physiological dephosphorylation reaction. Toward the BB site, sixty bromocatechol-chalcone derivatives were designed and synthesized as allosteric inhibitors of PTP1B against diabetes mellitus. The most potent compound LXQ-87 (C8) inhibited PTP1B noncompetitively with an IC₅₀ value of 1.061±0.202 μM. Oral administration of LXQ-87 reduces the fasting blood glucose level and improves glucose tolerance and dyslipidemia in BKS db/db mice suffering from T2DM. LXQ-87 alleviates insulin resistance and promotes cellular glucose uptake by directly binding to intracellular PTP1B.

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.