Pharmaceutical Institute, Pharmaceutical Chemistry I, PharmaCenter Bonn, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
J Med Chem. 2014 Aug 14;57(15):6679-703. doi: 10.1021/jm500729a. Epub 2014 Jul 16.
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, PSB-1491, IC50 human MAO-B 0.386 nM, >25000-fold selective versus MAO-A) and N-(3,4-dichlorophenyl)-1H-indole-5-carboxamide (53, PSB-1410, 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, PSB-1434, 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.
吲唑-和吲哚-甲酰胺被发现是高度有效、选择性、竞争性和可逆的单胺氧化酶 B（MAO-B）抑制剂。这些化合物可以通过标准的合成程序很容易地获得，总收率很高。最有效的衍生物是 N-(3,4-二氯苯基）-1-甲基-1H-吲唑-5-甲酰胺（38a，PSB-1491，IC50 对人 MAO-B 为 0.386 nM，对 MAO-A 的选择性>25000 倍）和 N-(3,4-二氯苯基）-1H-吲哚-5-甲酰胺（53，PSB-1410，IC50 对人 MAO-B 为 0.227 nM，对 MAO-A 的选择性>5700 倍）。用亚甲胺间隔基取代羧酰胺连接基得到（E）-N-(3,4-二氯苯基）-1-(1H-吲唑-5-基）亚甲胺（58），代表了一类具有高度有效和选择性的新型 MAO-B 抑制剂（IC50 对人 MAO-B 为 0.612 nM，对 MAO-A 的选择性>16000 倍）。在 N-(3,4-二氟苯基-1H-吲唑-5-甲酰胺（30，PSB-1434，IC50 对人 MAO-B 为 1.59 nM，对 MAO-A 的选择性>6000 倍）中，高活性和选择性与优越的物理化学性质最佳结合。计算对接研究深入了解了抑制剂与酶结合位点的相互作用，并为其尽管分子尺寸较小但仍具有高活性提供了依据。
