期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 74, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2022.117069
关键词
C-Abl; Molecular modeling; 4-methyl-3-(pyridin-2-ylamino)benzamide; Neuroprotective effect
资金
- National Natural Science Foundation of China [21603095]
- Guangdong Provincial Key Labo-ratory of Construction Foundation [2017B030314030, 2020B1212060034]
In this study, a series of 4-methyl-3-(pyridin-2-ylamino)benzamide derivatives were designed and synthesized. Compound 9a showed significant inhibitory activity against c-Abl and a potent neuroprotective effect against MPP+-induced cell death. It also exhibited lower cell toxicity compared to nilotinib and had higher oral bioavailability and proper blood-brain barrier permeability.
C-Abl is involved in various biological processes and plays an important role in neurodegenerative diseases, especially Parkinson's disease (PD). Previous studies have found that nilotinib shows a neuroprotective effect cell and animal models of PD by inhibiting the activation of c-Abl. But the low blood-brain barrier permeability and potential toxicity limit the further use of nilotinib in PD. Based on molecular modeling studies, a series of 4-methyl-3-(pyridin-2-ylamino)benzamide derivatives were designed and synthesized. In particular, compound 9a exhibited significant inhibitory activity against c-Abl and a potent neuroprotective effect against MPP+-induced SH-SY5Y cell death. Moreover, 9a not only displayed lower cell toxicity compared with nilotinib, but also showed higher oral bioavailability and proper permeability of the blood-brain barrier. This paper provides 4-methyl-3-(pyridin-2-ylamino)benzamide derivatives as a new scaffold for c-Abl inhibitor with potential neuro-protective effect.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据