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
  • 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: [email protected].
  • 3. School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. Electronic address: [email protected].
  • 4. School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China. Electronic address: [email protected].
  • 5. School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. Electronic address: [email protected].
  • 6. School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. Electronic address: [email protected].
  • 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: [email protected].
  • 8. School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. Electronic address: [email protected].
  • 9. School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China. Electronic address: [email protected].
  • 10. School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. Electronic address: [email protected].
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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