Indazole- and Indole-5- carboxamides: Selective and Reversible Monoamine Oxidase B Inhibitors with Subnanomolar Potency

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Indazol-5-carboxamides, indol-5- carboxamide, and (1H-indazol-5-yl)methanimine derivatives are described as structurally novel classes of selective MAO-B inhibitors. Structural optimization and SAR analyses led to the discovery of remarkably potent competitive and reversible MAO-B inhibitors with subnanomolar potency. Such compounds will be highly useful as pharmacological tools for in vitro and in vivo studies and may be suitable for the development of radioligands, including diagnostics for positron emission tomography (PET). Relevant structures are patented.



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, 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 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, 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 inhibitorsinteraction with the enzyme binding site and a rationale for their high potency despite their small molecular size.

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