title: Crystal structures, binding interactions, and ADME evaluation of brain penetrant N-substituted indazole-5-carboxamides as subnanomolar, selective monoamine oxidase B and dual MAO-A/B inhibitors.
abstract: The pharmacological and physicochemical analysis of structurally optimized N-alkyl-substituted indazole-5-carboxamides, developed as potential drug and radioligand candidates for the treatment and diagnosis of Parkinson's disease (PD) and other neurological disorders, is reported. Recent efforts have been focused on the development of subnanomolar potent, selective MAO-B (N1-alkyl-substituted compounds 12a-14a and 15) and dual active MAO-A/B (N2-methylated compounds 12b-14b) inhibitors with nanomolar potency towards MAO-B and moderately active against MAO-A enzyme, respectively. The most promising drug-like derivatives in both series were N-(3-chloro-4-fluorophenyl)-1-methyl-1H-indazole-5-carboxamide (13a, NTZ-1441, IC50hMAO-B 0.662 nM, >15000-fold selective versus MAO-A) and N-(3-chloro-4-fluorophenyl)-2-methyl-2H-indazole-5-carboxamide (13b, NTZ-1442, IC50hMAO-B 8.08 nM, IC50hMAO-A 0.56 μM, SI = 70). Moreover, compounds 13a and 13b were predicted to cross both the gastrointestinal tract (at pH 2.0, 5.5, and 7,4) and the blood-brain barrier (BBB) in vitro with appropriate drug-like properties required for CNS active drugs. Combined single X-ray/molecular modeling studies provided insights into the enzyme-inhibitor interactions within both MAO isoforms and the rationale for their inhibitory activity with controlled MAO-A/B selectivity - despite their small structural differences. The binding modes of 12a,b and 13a,b confirmed that the major interactions with hMAO-B were established via the flexible carbonyl group of the carboxamide linkage and the electron-donating nitrogens N1 or N2 of the indazole moiety, allowing further exploration of the alkyl side chain for next step lead optimization efforts.
authors.affiliation: NTZ Lab Ltd., Krasno selo 198, Sofia 1618, Bulgaria. Electronic address: ntzvetkov@ntzlab.com.
authors.forename: Nikolay T
authors.initials: NT
authors.lastname: Tzvetkov
authors.affiliation: Department of Chemistry, University of Bielefeld, Universitätsstr. 25, 33615 Bielefeld, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Stammler
authors.affiliation: Department of Chemistry, University of Bielefeld, Universitätsstr. 25, 33615 Bielefeld, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Neumann
authors.affiliation: Bulgarian Academy of Sciences, Institute of Organic Chemistry, Centre of Phytochemistry, Acad. G. Bonchev Str., Bl. 9, Sofia 1113, Bulgaria.
authors.forename: Silvia
authors.initials: S
authors.lastname: Hristova
authors.affiliation: Bulgarian Academy of Sciences, Institute of Organic Chemistry, Centre of Phytochemistry, Acad. G. Bonchev Str., Bl. 9, Sofia 1113, Bulgaria.
authors.forename: Liudmil
authors.initials: L
authors.lastname: Antonov
authors.affiliation: BioSolveIT GmbH, An der Ziegelei 79, 53757 St. Augustin, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Gastreich
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D018360:Crystallography, X-Ray; D041981:Gastrointestinal Tract / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D007700:Kinetics; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D010539:Permeability; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D012995:Solubility; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D007191:Indazoles; D008996:Monoamine Oxidase Inhibitors; D014867:Water; D008995:Monoamine Oxidase
keywords: ADME; Indazole-5-carboxamides; MAO inhibitors; Molecular modeling; Parkinson's disease; X-ray