title: Rational approaches towards reversible inhibition of type B monoamine oxidase. Design and evaluation of a novel 5H-Indeno[1,2-c]pyridazin-5-one derivative.
abstract: The stereoelectronic properties of several potent reversible monoamine oxidase B (MAO-B) inhibitors were studied with a view to develop a pharmacophore model for reversible MAO-B inhibition. This study suggested that important specific H-bond and hydrophobic interactions are required for potent and selective MAO-B inhibition. These requirements were applied in the design and synthesis of a novel reversible and selective MAO-B inhibitor, 3-methyl-8-(4,4,4-trifluoro-butoxy)indeno[1,2-c]pyridazin-5-one, that is ca. 7000 times more selective as an inhibitor for MAO-B than for MAO-A, with K(i(MAO-B)) in the low nanomolar range.
authors.affiliation: Facultés Universitaires Notre-Dame de la Paix, Laboratoire de Chimie Moléculaire Structurale, B-5000 Namur, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ooms
authors.forename: Raphaël
authors.initials: R
authors.lastname: Frédérick
authors.forename: François
authors.initials: F
authors.lastname: Durant
authors.forename: Jacobus P
authors.initials: JP
authors.lastname: Petzer
authors.forename: Neal
authors.initials: N
authors.lastname: Castagnoli
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Van der Schyf
authors.forename: Johan
authors.initials: J
authors.lastname: Wouters
mesh_terms: D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D008996:Monoamine Oxidase Inhibitors; D011724:Pyridazines; D008995:Monoamine Oxidase