title: Discovery of highly selective and potent monoamine oxidase B inhibitors: Contribution of additional phenyl rings introduced into 2-aryl-1,3,4-oxadiazin-5(6H)-one.
abstract: Monoamine oxidase B (MAO-B) is a flavin adenine dinucleotide (FAD)-containing enzyme that plays a major role in the oxidative deamination of biogenic amines and neurotransmitters. Inhibiting MAO-B activity is a promising approach in the treatment of neurological disorders. Here, we report a series of 2-aryl-1,3,4-oxadiazin-5(6H)-one derivatives as highly selective and potent MAO-B inhibitors. Analysis of the binding sites of hMAO-A and hMAO-B led to design of linear analogs of 2-aryl-1,3,4-oxadiazin-5(6H)-one with an additional phenyl ring. Biological evaluation of the 26 new derivatives resulted in the identification of highly potent and selective inhibitors with optimal physicochemical properties to potentially cross the blood-brain barrier (BBB). Compounds 18a, 18b, 18e and 25b potently inhibited MAO-B, with IC50values of 4-25 nM and excellent SI over MAO-A (18a > 25000, 18b > 8333 and 18e > 4000 and 25b > 4545). Docking results suggest that an optimal linker between two aromatic rings on the 2-aryl-1,3,4-oxadiazin-5(6H)-one scaffold is a key element in the binding and inhibition of MAO-B.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, South Korea.
authors.forename: Jungeun
authors.initials: J
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, South Korea.
authors.forename: Yeongcheol
authors.initials: Y
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, South Korea.
authors.forename: So Jung
authors.initials: SJ
authors.lastname: Park
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, South Korea.
authors.forename: Joohee
authors.initials: J
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, South Korea.
authors.forename: Yeong Shik
authors.initials: YS
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, South Korea.
authors.forename: Young-Ger
authors.initials: YG
authors.lastname: Suh
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, South Korea. Electronic address: jyleeut@snu.ac.kr.
authors.forename: Jeeyeon
authors.initials: J
authors.lastname: Lee
mesh_terms: D001555:Benzene Derivatives / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000187:drug effects*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D010069:Oxadiazoles / Q000737:chemistry* / Q000494:pharmacology; D012680:Sensitivity and Specificity
chemical_list: D001555:Benzene Derivatives; D008996:Monoamine Oxidase Inhibitors; D010069:Oxadiazoles; D008995:Monoamine Oxidase
keywords: Monoamine oxidase B; Optimal linker; Selectivity