Discovery of arylbenzylamines as PDE4 inhibitors with potential neuroprotective effect
Discovery of arylbenzylamines as PDE4 inhibitors with potential neuroprotective effect
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发现具有潜在神经保护作用的 PDE4 抑制剂芳基苄胺
DOI：
10.1016/j.ejmech.2019.02.026
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发表时间：
2019
影响因子：
6.7
通讯作者：
Zhou Zhong-Zhen
中科院分区：
文献类型：
--
作者：
Tang Lv;Huang Chang;Zhong Jiahong;He JiaPeng;Guo Jiayin;Liu Menghua;Xu Jiang-Ping;Wang Hai-Tao;Zhou Zhong-Zhen
越来越多的证据证实了PDE4抑制剂治疗帕金森病的潜力。我们报道的PDE4抑制剂FCPR16和FCPR03在SH-SY5Y细胞中显示了神经保护作用，但口服生物利用度很低。为了获得生物利用度更高的类似物，设计并合成了一系列新的芳基苄胺类化合物。初步筛选结果表明，含吡啶-3-胺侧链的芳基苄胺类化合物对人PDE4B1和PDE4D7亚型具有良好的抑制活性。此外，动力学研究表明，具有中纳分子IC50值的最有效的化合物11/11部分与PDE4B1结合(Imax分别为 的93%和90%)。分子对接结果揭示了化合物11与PDE4B1上游保守区2(UCR2)可能的相互作用，阐明了它们对PDE4部分抑制的可能原因。在以细胞为基础的PD模型中，化合物11和11可减轻MPP+(1-甲基-4-苯基吡啶)诱导的SH-SY5Y细胞凋亡，其神经保护作用强于PDE4抑制剂罗利普兰。此外，复方11r的口服生物利用度(8.20%)几乎是FCPR03(1.23%)的7倍。
Growing evidence confirms the potential of PDE4 inhibitors for the treatment of Parkinson's disease. Our reported PDE4 inhibitors FCPR16 and FCPR03 have displayed neuroprotective effects in SH-SY5Y cells, but have very low oral bioavailability. To access analogues with improved bioavailability, a new series of arylbenzylamine derivatives were designed and synthesized. Preliminary screening results of the series showed that arylbenzylamine derivatives bearing a pyridin-3-amine side chain displayed good inhibitory activities against human PDE4B1 and PDE4D7 isoforms. Moreover, kinetic studies revealed that the most potent compounds11rand11swith mid-nanomolar IC50values partially bind to PDE4B1 (Imax= 93% and 90% respectively). Molecular docking results revealed the possible interactions of compounds11rand11swith upstream conserved region 2 (UCR2) of PDE4B1, which illuminate possible reasons for their partial inhibition against PDE4. Using a cell-based model of PD, compounds11rand11swere found to alleviate cellular apoptosis in SH-SY5Y cells induced by MPP+(1-methyl-4-phenylpyridinium), with this neuroprotective effect being greater than PDE4 inhibitor rolipram. Furthermore, compound11rdisplayed nearly sevenfold oral bioavailability (8.20%) than FCPR03 (1.23%).