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Indazole- and indole-5-carboxamides: selective and reversible monoamine oxidase B inhibitors with subnanomolar potency.
J Med Chem. 2014 Aug 14;57(15):6679-703.
Nikolay T. Tzvetkov,a* Sonja Hinz,b Petra Küppers,b Marcus Gastreich,c Christa E. Müllerb
aUniversity of Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry II, Bonn, Germany
aPharmaCenter Bonn, University of Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Bonn, Germany
bBioSolveIT GmbH, An der Ziegelei 79, 53757 St. Augustin, Germany
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 (NTZ-1091; former PSB-1491, IC50 human MAO-B 0.386 nM, >25000-fold selective versus MAO-A) and N-(3,4-dichlorophenyl)-1H-indole-5-carboxamide (NTZ-1010, IC50 human MAO-B 0.227 nM, >5700-fold selective versus MAO-A). Replacement of the carboxamide linker with a methanimine spacer led a further novel class of highly potent and selective MAO-B inhibitors. In N-(3,4-difluorophenyl-1H-indazole-5-carboxamide (NTZ-1034, 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.
PMID: 24955776
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Monoamine oxidases (МАО, EC 1.4.3.4) are flavin adenine dinucleotide (FAD) containing enzymes localized on the mitochondrial outer membrane, which catalyze the oxidative deamination of biogenic amines and monoamine neurotransmitters.Two isoforms of MAO are present in most mammalian tissues, MAO-A and MAO-B, distinguished by their substrate and inhibitor selectivity [1;2]. The reaction catalyzed by MAO results in the production of hydrogen peroxide (H2O2) and other reactive oxygen species (ROS), which may contribute to oxidative stress and cell damage [3]. The activity and the expression levels of MAO-B in the human brain, but not those of MAO-A, increase with aging and may be associated with the loss of dopaminergic neurons in the substantia nigra, where MAO-B is the main form in glial cells [4]. The relationship between oxidative stress and progressive neuronal impairment indicates that inhibition of MAO-B activity may have neuroprotective effects [4;5]. Therefore, MAO-B inhibitors may be useful for the treatment of other neurodegenerative diseases as well including Alzheimer´s disease (AD) [6].
Reversible inhibition is expected to have considerable advantages compared to irreversible inhibition [7]. In the present study, novel classes of most potent reversible MAO-B inhibitors were discovered, namely indazole-5-carboxamides (designated class I), indole-5-carboxamides (class II) and (indazol-5-yl)methanimine derivatives (class III). The new compounds were evaluated at rat and human MAO A and B, and optimized in order to improve their MAO-B affinity and selectivity, as well as their physicochemical and drug-like properties. Computational studies were performed to understand their binding modes and to explain their exceedingly high affinities.
The indazol-5-carboxamide scaffold served as a starting point for the design, synthesis and biological evaluation of a number of compounds, many of them with MAO-B inhibitory activity in the subnanomolar range and significantly improved physicochemical properties. We also prepared two additional classes of MAO-B inhibitors either by replacement of the 5-substituted indazole by a 5-substituted indole (class II), or by exchange of the amide connection by a methanimine linker (class III).
As the most promising MAO-B inhibitors of the present series with drug-like properties, two compounds have to be highlighted (Figure 1).