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Discovery of a novel class of potent coumarin monoamine oxidase B inhibitors

Pisani, Leonardo
Muncipinto, Giovanni
Miscioscia, Teresa Fabiola
Nicolotti, Orazio
Leonetti, Francesco
Catto, Marco
Caccia, Carla
Salvati, Patricia
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Published in Journal of medicinal chemistry. 2009, vol. 52, no. 21, p. 6685-706
Abstract 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.
PMID: 19810674
Note sous-titre : development and biopharmacological profiling of 7-[(3-chlorobenzyl)oxy]-4-[(methylamino)methyl]-2H-chromen-2-one methanesulfonate (NW-1772) as a highly potent, selective, reversible, and orally active monoamine oxidase B inhibitor
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PISANI, Leonardo et al. Discovery of a novel class of potent coumarin monoamine oxidase B inhibitors. In: Journal of medicinal chemistry, 2009, vol. 52, n° 21, p. 6685-706. doi: 10.1021/jm9010127 https://archive-ouverte.unige.ch/unige:4066

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Deposited on : 2009-11-20

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