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

Document created by ntzvetkov on Oct 11, 2014Last modified by ntzvetkov on Mar 13, 2015
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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. For further information please contact   the Corresponding   Author: *Phone:   +49-179-5284358. E-mail:





  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,   IC50 human   MAO-B 0.386 nM, >25000-fold selective versus MAO-A)   and N-(3,4-dichlorophenyl)-1H-indole-5-carboxamide   (53,   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 inhibitors’ interaction   with the enzyme binding site and a rationale for their high   potency despite their small molecular size. 

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