Synthesis and evaluation of biaryl derivatives for structural characterization of selective monoamine oxidase B Inhibitors toward Parkinson’s disease therapy
- Synthesis and evaluation of biaryl derivatives for structural characterization of selective monoamine oxidase B Inhibitors toward Parkinson’s disease therapy
- 배애님; 박기덕; 박종현; 최지원; 연슬기; 신수정; 김현정; 김시원; 이예림; 장보고; 반용선; 한균희; 이용섭
- Issue Date
- Bioorganic & medicinal chemistry
- VOL 26, NO 1-244
- Benzyloxyphenyl moiety is a common structure of highly potent, selective and reversible inhibitors of monoamine oxidase B (MAO-B), safinamide and sembragiline. We synthesized 4-(benzyloxy)phenyl and biphenyl-4-yl derivatives including halogen substituents on the terminal aryl unit. In addition, we modified the carbon linker between amine group and the biaryl linked unit. Among synthesized compounds, 12c exhibited the most potent and selective MAO-B inhibitory effect (hMAO-B IC50: 8.9 nM; >10,000-fold selectivity over MAO-A) as a competitive inhibitor. In addition, 12c showed greater MAOB inhibitory activity and selectivity compared to well-known MAO-B inhibitors such as selegiline, safinamide and sembragiline. In the MPTP-induced mouse model of Parkinson’s disease (PD), 12c significantly protected the tyrosine hydroxylase (TH)-immunopositive DAergic neurons and attenuated the PD-associated behavioral deficits. This study suggests characteristic structures as a MAO-B inhibitor that may provide a good insight for the development of therapeutic agents for PD.
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