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Eur J Med Chem. 2017 Feb 15;127:470-492. doi: 10.1016/j.ejmech.2017.01.011. Epub 2017 Jan 11.

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.

Author information

1
NTZ Lab Ltd., Krasno selo 198, Sofia 1618, Bulgaria. Electronic address: ntzvetkov@ntzlab.com.
2
Department of Chemistry, University of Bielefeld, Universitätsstr. 25, 33615 Bielefeld, Germany.
3
Bulgarian Academy of Sciences, Institute of Organic Chemistry, Centre of Phytochemistry, Acad. G. Bonchev Str., Bl. 9, Sofia 1113, Bulgaria.
4
BioSolveIT GmbH, An der Ziegelei 79, 53757 St. Augustin, Germany.

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, IC50 hMAO-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, IC50 hMAO-B 8.08 nM, IC50 hMAO-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.

KEYWORDS:

ADME; Indazole-5-carboxamides; MAO inhibitors; Molecular modeling; Parkinson's disease; X-ray

PMID:
28107736
DOI:
10.1016/j.ejmech.2017.01.011
[Indexed for MEDLINE]

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