Inhibition of neuronal nitric oxide synthase (nNOS) is a promising therapeutic approach to treat neurodegenerative diseases. Recently, we have achieved considerable progress in improving the potency and isoform selectivity of human nNOS inhibitors bearing a 2-aminopyridine scaffold. However, these inhibitors still suffered from too low cell membrane permeability to enter into CNS drug development. We report herein our studies to improve permeability of nNOS inhibitors as measured by both PAMPA–BBB and Caco-2 assays. The most permeable compound (12) in this study still preserves excellent potency with human nNOS (K_i = 30 nM) and very high selectivity over other NOS isoforms, especially human eNOS (hnNOS/heNOS = 2799, the highest hnNOS/heNOS ratio we have obtained to date). X-ray crystallographic analysis reveals that 12 adopts a similar binding mode in both rat and human nNOS, in which the 2-aminopyridine and the fluorobenzene linker form crucial hydrogen bonds with glutamate and tyrosine residues, respectively.

中文翻译：

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使用有效的和选择性的2-氨基吡啶基支架与氟苯连接基改善人类神经元一氧化氮合酶抑制剂的细胞通透性

抑制神经元一氧化氮合酶（nNOS）是治疗神经退行性疾病的一种有前途的治疗方法。近来，我们在改善带有2-氨基吡啶支架的人nNOS抑制剂的效力和同工型选择性方面取得了相当大的进步。然而，这些抑制剂仍然具有太低的细胞膜通透性以至于不能参与CNS药物开发。我们在此报告我们的研究，以通过PAMPA–BBB和Caco-2分析来提高nNOS抑制剂的通透性。这项研究中最具渗透性的化合物（12）仍保留了与人nNOS（K _i= 30 nM）和对其他NOS亚型，特别是人类eNOS的很高的选择性（hnNOS / heNOS = 2799，迄今为止我们获得的最高hnNOS / heNOS比值）。X射线晶体学分析表明12在大鼠和人的nNOS中采用相似的结合模式，其中2-氨基吡啶和氟苯连接子分别与谷氨酸和酪氨酸残基形成关键的氢键。