化学
神经保护
生物利用度
IC50型
角色扮演
结构-活动关系
SH-SY5Y型
药理学
对接(动物)
立体化学
生物化学
酶抑制剂
体外
酶
细胞培养
神经母细胞瘤
生物
护理部
医学
磷酸二酯酶
遗传学
作者
Lv Tang,Chang Huang,Jiahong Zhong,Jiapeng He,Jiayin Guo,Menghua Liu,Jiangping Xu,Haitao Wang,Zhong‐Zhen Zhou
标识
DOI:10.1016/j.ejmech.2019.02.026
摘要
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 compounds 11r and 11s with mid-nanomolar IC50 values partially bind to PDE4B1 (Imax = 93% and 90% respectively). Molecular docking results revealed the possible interactions of compounds 11r and 11s with upstream conserved region 2 (UCR2) of PDE4B1, which illuminate possible reasons for their partial inhibition against PDE4. Using a cell-based model of PD, compounds 11r and 11s were 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, compound 11r displayed nearly sevenfold oral bioavailability (8.20%) than FCPR03 (1.23%).
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