2. Academic Validation
  3. Design, synthesis and evaluation of novel monoamine oxidase B (MAO-B) inhibitors with improved pharmacokinetic properties for Parkinson's disease

Design, synthesis and evaluation of novel monoamine oxidase B (MAO-B) inhibitors with improved pharmacokinetic properties for Parkinson's disease

  • Eur J Med Chem. 2023 Apr 5;252:115308. doi: 10.1016/j.ejmech.2023.115308.
Chao Yi 1,  Xinchang Liu 2,  Kangzhi Chen 1,  Haiping Liang 1,  Chuanfei Jin 3
Affiliations

Affiliations

  • 1 HEC Pharm Group, HEC Research and Development Center, Dongguan, 523871, People's Republic of China.
  • 2 HEC Pharm Group, HEC Research and Development Center, Dongguan, 523871, People's Republic of China; Key Lab of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Wushan Rd-381, Guangzhou 510641, People's Republic of China.
  • 3 HEC Pharm Group, HEC Research and Development Center, Dongguan, 523871, People's Republic of China; Sunshine Lake Pharma Co. Ltd., Shenzhen, 518000, People's Republic of China. Electronic address: chuanfeijin@163.com.
PMID: 37001389 DOI: 10.1016/j.ejmech.2023.115308
Abstract

A series of novel ((benzofuran-5-yl)methyl)pyrrolidine-2-carboxamide derivatives were designed, synthesized and evaluated as MAO-B inhibitors. SAR studies indicated that cyclizing benzyl ether into benzofuran ring resulted in the most potent MAO-B Inhibitor (IC50 = 0.037 μM), (2S,4S)-4-fluoro-1-((2-(4-fluorophenyl) benzofuran-5-yl)methyl)pyrrolidine-2-carboxamide (C14). PK properties of C14 in rats and mice were significantly improved compared to our previous candidate and safinamide, indicating that benzofuran moiety is essential for improving PK properties. Moreover, C14 displayed good metabolic stability and brain-blood barrier permeability, as well as favorable in vitro properties. Finally, C14 significantly inhibited MAO-B in the mouse brain. C14 exhibited a potential efficacy for DA deficits in the MPTP-induced mouse model and significantly increased DA concentration in the striatum. Thus, we identified that C14 may be a promising drug candidate for PD treatment.

Keywords

Benzofuran; Monoamine oxidase B inhibitors; Parkinson's disease; Safinamide.

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