Key Laboratory of Traditional Chinese Medicine Research and Development of Hebei Province, Institute of Traditional Chinese Medicine, Chengde Medical University, Chengde 067000, Hebei, China.
Department of Pathogen Biology, Chengde Medical University, Chengde 067000, Hebei, China.
Bioorg Chem. 2022 Dec;129:106120. doi: 10.1016/j.bioorg.2022.106120. Epub 2022 Sep 3.
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 (IC = 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 (IC = 0.09 ± 0.002 µM), which was relatively close to that of positive control ingliforib (IC = 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.
本研究旨在评估 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 和 IV），得到了 31 种新型 GP 抑制剂。SAR 研究表明，5-氯吲哚与苯并六元杂环的缀合物被发现能提高活性。特别是化合物 IIIh（IC = 0.21 ± 0.03 µM）对 RMGPa 的活性最强，其效力约为 PSN-357 的两倍。为了筛选出一种适合体内活性测试的化合物，我们进一步进行了对三种不同亚型的 GPa（HLGPa、HMGPa 和 HBGPa）的抑制作用实验和相应的亲和实验。结果表明，化合物 IIIh 对上述三种亚型的 GP 具有很强的抑制活性，特别是对 HBGPa（IC = 0.09 ± 0.002 µM），与阳性对照 ingliforib（IC = 0.16 ± 0.02 µM）相当接近。化合物 IIIh 对 HBGPa 的亲和力是 HLGPa 的 4.3 倍，是 HMGPa 的 1.1 倍。这一事实进一步证明，化合物 IIIh 对 HMGPa 的抑制作用强于其他两种亚型。此外，体内活性评价表明，化合物 IIIh 对 MI/R 损伤小鼠具有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。
