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
  • 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: [email protected].
  • 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: [email protected].
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.