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  3. A highly effective and stable butyrylcholinesterase inhibitor with multi-faceted neuroprotection and cognition improvement

A highly effective and stable butyrylcholinesterase inhibitor with multi-faceted neuroprotection and cognition improvement

  • Eur J Med Chem. 2022 Sep 5;239:114510. doi: 10.1016/j.ejmech.2022.114510.
Qi Li 1,  Baichen Xiong 2,  Yuanyuan Wang 2,  Weiping Lyu 2,  Shuaishuai Xing 2,  Ying Chen 3,  Qinghong Liao 3,  Siyu He 4,  Feng Feng 5,  Wenyuan Liu 2,  Yao Chen 6,  Haopeng Sun 7
Affiliations

Affiliations

  • 1 School of Basic Medicine, Qingdao University, Qingdao, 266071, People's Republic of China.
  • 2 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
  • 3 Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
  • 4 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.
  • 5 Jiangsu Drug Development Engineering Research Center for Central Degenerative Disease, Jiangsu Food and Pharmaceuticals Science College, 223005, People's Republic of China; Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
  • 6 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China. Electronic address: 300630@njucm.edu.cn.
  • 7 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. Electronic address: sunhaopeng@cpu.edu.cn.
PMID: 35728508 DOI: 10.1016/j.ejmech.2022.114510
Abstract

Butyrylcholinesterase (BChE) has been more and more attractive for treating neurodegenerative diseases, especially Alzheimer's disease (AD). In this study, we conducted activity and druggability optimization based on the structures that were previously reported. Most compounds exhibited pronounced BChE inhibitory capacity with nanomolar IC50 values. Based on the results of inhibiting activity and cyto-safety evaluations, two compounds (7, eqBChE IC50 = 2.94 nM, hBChE IC50 = 34.6 nM, and 20, eqBChE IC50 = 0.15 nM, hBChE IC50 = 45.2 nM) have been selected as candidates. High stability of compound 20 contributed to significantly improved blood concentration and tissue exposure, resulting in a reduced administration and effective dose in pharmacodynamic experiments. Two candidates exhibited remarkable neuroprotective properties and cognition improving activity, by benefiting cholinergic system, reducing the total Aβ amount and increasing the ghrelin content. Simultaneous modulation in the center and periphery greatly improves the efficiency of BChE inhibitors. Considering the regulation on ghrelin level, BChE inhibition could improve not only symptoms but also nutritional status of AD patients.

Keywords

Cognitive improvement; Neuroprotection; Selective butyrylcholinesterase inhibitor.

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