2. Academic Validation
  3. Discovery of 4-benzylpiperazinequinoline BChE inhibitor that suppresses neuroinflammation for the treatment of Alzheimer's disease

Discovery of 4-benzylpiperazinequinoline BChE inhibitor that suppresses neuroinflammation for the treatment of Alzheimer's disease

  • Eur J Med Chem. 2024 Jun 5:272:116463. doi: 10.1016/j.ejmech.2024.116463.
Ying Chen 1,  Weiting Zhang 2,  Qi Li 2,  Huanfang Xie 2,  Shuaishuai Xing 2,  Xin Lu 2,  Weiping Lyu 2,  Baichen Xiong 2,  Yuanyuan Wang 2,  Wei Qu 3,  Wenyuan Liu 2,  Heng Chi 4,  Xiaolong Zhang 4,  Feng Feng 5,  Haopeng Sun 6
Affiliations

Affiliations

  • 1 Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China.
  • 2 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
  • 3 School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
  • 4 Jiangsu Drug Development Engineering Center for Central Degenerative Disease, Jiangsu Food and Pharmaceuticals Science College, 223005, China.
  • 5 School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China; Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: fengfeng@cpu.edu.cn.
  • 6 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: sunhaopeng@cpu.edu.cn.
PMID: 38704944 DOI: 10.1016/j.ejmech.2024.116463
Abstract

Butyrylcholinesterase (BChE) has attracted wide interest as a promising target in Alzheimer's disease (AD) investigation. BChE is considered to play a compensable role of hydrolyzing acetylcholine (ACh), and its positive correlation with β-amyloid (Aβ) deposition also promotes disease progression. Herein, we uncovered a selective potent BChE Inhibitor S21-1011 (eqBChE IC50 = 0.059 ± 0.006 μM, hBChE IC50 = 0.162 ± 0.069 μM), which presented satisfactory druggability and therapeutic efficacy in AD models. In pharmacokinetics (PK) studies, S21-1011 showed excellent blood-brain barrier (BBB) permeability, metabolism stability and high oral-bioavailability. In pharmacodynamic (PD) studies, it protected neural cells from toxicity and inflammation stimulation in vitro. Besides, it also exerted anti-inflammatory effect and alleviated cognitive impairment in mice models induced by lipopolysaccharides (LPS) and Aβ. Generally, this compound has been confirmed to function as a neuroprotector and cognition improver in various AD pathology-like models. Therefore, S21-1011, a novel potent BChE Inhibitor, could be considered as a potential anti-AD candidate worthy of more profound investigation.

Keywords

Alzheimer's disease (AD); Butyrylcholinesterase (BChE); Neuroprotector; Oxidative stress; Small molecule inhibitors; Targeted therapy.

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