title: Indazole- and indole-5-carboxamides: selective and reversible monoamine oxidase B inhibitors with subnanomolar potency.
abstract: Indazole- and indole-carboxamides were discovered as highly potent, selective, competitive, and reversible inhibitors of monoamine oxidase B (MAO-B). The compounds are easily accessible by standard synthetic procedures with high overall yields. The most potent derivatives were N-(3,4-dichlorophenyl)-1-methyl-1H-indazole-5-carboxamide (38a, PSB-1491, IC50 human MAO-B 0.386 nM, >25000-fold selective versus MAO-A) and N-(3,4-dichlorophenyl)-1H-indole-5-carboxamide (53, PSB-1410, IC50 human MAO-B 0.227 nM, >5700-fold selective versus MAO-A). Replacement of the carboxamide linker with a methanimine spacer leading to (E)-N-(3,4-dichlorophenyl)-1-(1H-indazol-5-yl)methanimine (58) represents a further novel class of highly potent and selective MAO-B inhibitors (IC50 human MAO-B 0.612 nM, >16000-fold selective versus MAO-A). In N-(3,4-difluorophenyl-1H-indazole-5-carboxamide (30, PSB-1434, IC50 human MAO-B 1.59 nM, selectivity versus MAO-A>6000-fold), high potency and selectivity are optimally combined with superior physicochemical properties. Computational docking studies provided insights into the inhibitors' interaction with the enzyme binding site and a rationale for their high potency despite their small molecular size.
authors: Pharmaceutical Institute, Pharmaceutical Chemistry I, PharmaCenter Bonn, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
authors: Nikolay T
authors: NT
authors: Tzvetkov
authors: Sonja
authors: S
authors: Hinz
authors: Petra
authors: P
authors: Küppers
authors: Marcus
authors: M
authors: Gastreich
authors: Christa E
authors: CE
authors: Müller
mesh_terms: D000818:Animals; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000737:chemistry*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D011485:Protein Binding; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007191:Indazoles; D007211:Indoles; D008996:Monoamine Oxidase Inhibitors; C000595000:N-(3,4-dichlorophenyl)-1-methyl-1H-indazole-5-carboxamide; C000595001:N-(3,4-dichlorophenyl)-1H-indole-5-carboxamide; D011994:Recombinant Proteins; D008995:Monoamine Oxidase