Design, synthesis and evaluation of novel monoamine oxidase B (MAO-B) inhibitors with improved pharmacokinetic properties for Parkinson's disease.
Eur J Med Chem
; 252: 115308, 2023 Apr 05.
Article
em En
| MEDLINE
| ID: mdl-37001389
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
/
Benzofuranos
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article