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Discovery of novel heterocyclic derivatives as potential glycogen phosphorylase inhibitors with a cardioprotective effect
Bioorganic Chemistry ( IF 5.1 ) Pub Date : 2022-09-03 , DOI: 10.1016/j.bioorg.2022.106120
Zhiwei Yan 1 , Shuai Li 1 , Youde Wang 1 , Jing Li 1 , Can Ma 1 , Yachun Guo 2 , Liying Zhang 1
Affiliation  

The purpose of this study was to evaluate the effect of GP inhibitor as a potential pharmaceutical target on MI/R injury. Four different structural types of novel compounds (I, II, III, and IV) were designed and synthesized, obtaining 31 novel GP inhibitors. SAR studies revealed that the conjugates of 5-chloroindole with benzo six-membered heterocyclic were found to elevate the activity. In particular, compound IIIh (IC50 = 0.21 ± 0.03 µM) emerged as a potent derivative against RMGPa, being approximately 2-fold less potent than that of PSN-357. In order to screen out a compound for in vivo activity test, we further conducted an experiment of inhibition against three different subtypes of GPa (HLGPa, HMGPa and HBGPa) and the corresponding affinity experiment. As a result, compound IIIh showed strong inhibitory activity against the above three subtypes of GP, especially on HBGPa (IC50 = 0.09 ± 0.002 µM), which was relatively close to that of positive control ingliforib (IC50 = 0.16 ± 0.02 µM). The affinity of compound IIIh to HBGPa was 4.3 times higher than that of HLGPa, and 1.1 times higher than that of HMGPa. This fact further proved that compound IIIh has a higher inhibitory effect on HMGPa than the other two subtypes. Besides, in vivo activity evaluation demonstrated that compound IIIh exhibited obviously cardioprotective effect on MI/R injury mice. The discovery of compound IIIh provides a new strategy for developing novel GP inhibitors with myocardial ischemia protection.



中文翻译:

发现新型杂环衍生物作为具有心脏保护作用的潜在糖原磷酸化酶抑制剂

本研究的目的是评估 GP 抑制剂作为潜在药物靶点对 MI/R 损伤的影响。设计并合成了四种不同结构类型的新型化合物(Ⅰ、Ⅱ、Ⅲ、,获得了31种新型GP抑制剂。SAR 研究表明,发现 5-氯吲哚与苯并六元杂环的缀合物可提高活性。特别是,化合物IIIh (IC 50  = 0.21 ± 0.03 µM) 作为一种有效的 RMGPa 衍生物出现,其效力比 PSN-357 低约 2 倍。为了筛选出一种化合物用于体内活性测试后,我们进一步进行了对三种不同GPa亚型(HLGPa、HMGPa和HBGPa)的抑制实验和相应的亲和实验。因此,化合物IIIh对上述三种 GP 亚型均表现出较强的抑制活性,尤其是对 HBGPa(IC 50  = 0.09 ± 0.002 µM),与阳性对照 ingliforib(IC 50  = 0.16 ± 0.02 µM)比较接近. 化合物IIIh对HBGPa的亲和力HLGPa高4.3倍,比HMGPa高1.1倍。这一事实进一步证明化合物IIIh对HMGPa的抑制作用高于其他两种亚型。此外,体内活性评价表明化合物IIIh对MI/R损伤小鼠表现出明显的心脏保护作用。化合物IIIh的发现为开发具有心肌缺血保护作用的新型GP抑制剂提供了新策略。

更新日期:2022-09-03
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