Discovery of a Novel Class of Potent Coumarin Monoamine Oxidase B Inhibitors: Development and Biopharmacological Profiling of 7-[(3-Chlorobenzyl)oxy]-4-[(methylamino)methyl]-2H-chromen-2-one Me
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- 作者：Leonardo Pisani ; Giovanni Muncipinto ; Teresa Fabiola Miscioscia ; Orazio Nicolotti ; Francesco Leonetti ; Marco Catto ; Carla Caccia ; Patricia Salvati ; Ramon Soto-Otero ; Estefania Mendez-Alvarez ; Celine P
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：November 12, 2009
- 年：2009
- 卷：52
- 期：21
- 页码：6685-6706
- 全文大小：1364K
- 年卷期：v.52,no.21(November 12, 2009)
- ISSN：1520-4804
文摘
In an effort to discover novel selective monoamine oxidase (MAO) B inhibitors with favorable physicochemical and pharmacokinetic profiles, 7-[(m-halogeno)benzyloxy]coumarins bearing properly selected polar substituents at position 4 were designed, synthesized, and evaluated as MAO inhibitors. Several compounds with MAO-B inhibitory activity in the nanomolar range and excellent MAO-B selectivity (selectivity index SI > 400) were identified. Structure−affinity relationships and docking simulations provided valuable insights into the enzyme−inhibitor binding interactions at position 4, which has been poorly explored. Furthermore, computational and experimental studies led to the identification and biopharmacological characterization of 7-[(3-chlorobenzyl)oxy]-4-[(methylamino)methyl]-2H-chromen-2-one methanesulfonate 22b (NW-1772) as an in vitro and in vivo potent and selective MAO-B inhibitor, with rapid blood−brain barrier penetration, short-acting and reversible inhibitory activity, slight inhibition of selected cytochrome P450s, and low in vitro toxicity. On the basis of this preliminary preclinical profile, inhibitor 22b might be viewed as a promising clinical candidate for the treatment of neurodegenerative diseases.