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  3. Optimizing drug-like properties of selective butyrylcholinesterase inhibitors for cognitive improvement: Enhancing aqueous solubility by disrupting molecular plane

Optimizing drug-like properties of selective butyrylcholinesterase inhibitors for cognitive improvement: Enhancing aqueous solubility by disrupting molecular plane

  • Eur J Med Chem. 2024 Mar 2:268:116289. doi: 10.1016/j.ejmech.2024.116289.
Shuaishuai Xing 1,  Xu Tang 1,  Leyan Wang 2,  Jun Wang 3,  Bingbing Lv 4,  Xiaolong Wang 5,  Can Guo 6,  Ye Zhao 1,  Feng Feng 7,  Wenyuan Liu 8,  Yao Chen 9,  Haopeng Sun 10
Affiliations

Affiliations

  • 1 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
  • 2 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. Electronic address: wangleyan02@163.com.
  • 3 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. Electronic address: 2020201407@stu.cpu.edu.cn.
  • 4 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China. Electronic address: 20220834@njucm.edu.cn.
  • 5 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. Electronic address: 3223010064@stu.cpu.edu.cn.
  • 6 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. Electronic address: guocan@stu.cpu.edu.cn.
  • 7 School of Pharmacy, Nanjing Medical University, 211166, Nanjing, People's Republic of China; Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. Electronic address: fengfeng@cpu.edu.cn.
  • 8 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. Electronic address: liuwenyuan@cpu.edu.cn.
  • 9 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China. Electronic address: 300630@njucm.edu.cn.
  • 10 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. Electronic address: sunhaopeng@cpu.edu.cn.
PMID: 38452730 DOI: 10.1016/j.ejmech.2024.116289
Abstract

Most recently, worldwide interest in butyrylcholinesterase (BChE) as a potential target for treating Alzheimer's disease (AD) has increased. In this study, the previously obtained selective BChE inhibitors with benzimidazole-oxadiazole scaffold were further structurally modified to increase their aqueous solubility and pharmacokinetic (PK) characteristics. S16-1029 showed improved solubility (3280 μM, upgraded by 14 times) and PK parameters, including plasma exposure (AUC0-inf = 1729.95 ng/mL*h, upgraded by 2.6 times) and oral bioavailability (Fpo = 48.18%, upgraded by 2 times). S16-1029 also displayed weak or no inhibition against Cytochrome P450 (CYP450) and human ether a-go-go related gene (hERG) Potassium Channel. In vivo experiments on tissue distribution revealed that S16-1029 could cross the blood-brain barrier (BBB) and reach the central nervous system (CNS). In vivo cognitive improvement efficacy and good in vitro target inhibitory activity (eqBChE IC50 = 11.35 ± 4.84 nM, hBChE IC50 = 48.1 ± 11.4 nM) were also assured. The neuroprotective effects against several AD pathology characteristics allowed S16-1029 to successfully protect the CNS of progressed AD patients. According to the findings of this study, altering molecular planarity might be a viable strategy for improving the drug-like property of CNS-treating drugs.

Keywords

Alzheimer's disease; Drug-like property optimization; Pharmacokinetic; Selective butyrylcholinesterase inhibitor; Solubility optimization.

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