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 methanesulfonate (NW-1772) as a highly potent, selective, reversible, and orally active monoamine oxidase B inhibitor.
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.
Pisani
Leonardo
L
Dipartimento Farmacochimico, Universita degli Studi di Bari, Via Orabona 4, 70125-Bari, Italy.
Muncipinto
Giovanni
G
Miscioscia
Teresa Fabiola
TF
Nicolotti
Orazio
O
Leonetti
Francesco
F
Catto
Marco
M
Caccia
Carla
C
Salvati
Patricia
P
Soto-Otero
Ramon
R
Mendez-Alvarez
Estefania
E
Passeleu
Celine
C
Carotti
Angelo
A
D000284:Administration, Oral; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008567:Membranes, Artificial; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010539:Permeability; D011485:Protein Binding; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship
C545540:7-((3-chlorobenzyl)oxy)-4-((methylamino)methyl)-2H-chromen-2-one; D003374:Coumarins; D007527:Isoenzymes; D008567:Membranes, Artificial; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase