2. Academic Validation
  3. Discovery of 4-methyl-3-(pyridin-2-ylamino)benzamide derivatives as C-Abl inhibitors with potential neuroprotective effect

Discovery of 4-methyl-3-(pyridin-2-ylamino)benzamide derivatives as C-Abl inhibitors with potential neuroprotective effect

  • Bioorg Med Chem. 2022 Nov 15:74:117069. doi: 10.1016/j.bmc.2022.117069.
Zichao Yang 1,  Yangcheng Ai 1,  Shanhe Wan 1,  Zilong Yang 1,  Honghao Li 2,  Zhonghuang Li 1,  Chunhui Huang 1,  Lishun Zhang 3,  Mingxia Li 1,  Jiajie Zhang 4,  Tingting Zhang 5
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2 Department of Chemistry & Biochemistry, University of California Santa Barbara, California 93106-9510, USA.
  • 3 Department of Pharmacy, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
  • 4 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: zhangjj@smu.edu.cn.
  • 5 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, China. Electronic address: zhangttgre@163.com.
PMID: 36283251 DOI: 10.1016/j.bmc.2022.117069
Abstract

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 in 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 neuroprotective effect.

Keywords

4-methyl-3-(pyridin-2-ylamino)benzamide; C-Abl; Molecular modeling; Neuroprotective effect.

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