Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States.
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California 92697-3900, United States.
J Med Chem. 2020 May 14;63(9):4528-4554. doi: 10.1021/acs.jmedchem.9b01573. Epub 2020 Apr 17.
Inhibition of neuronal nitric oxide synthase (nNOS), an enzyme implicated in neurodegenerative disorders, is an attractive strategy for treating or preventing these diseases. We previously developed several classes of 2-aminoquinoline-based nNOS inhibitors, but these compounds had drawbacks including off-target promiscuity, low activity against human nNOS, and only modest selectivity for nNOS over related enzymes. In this study, we synthesized new nNOS inhibitors based on 7-phenyl-2-aminoquinoline and assayed them against rat and human nNOS, human eNOS, and murine and (in some cases) human iNOS. Compounds with a -relationship between the aminoquinoline and a positively charged tail moiety were potent and had up to nearly 900-fold selectivity for human nNOS over human eNOS. X-ray crystallography indicates that the amino groups of some compounds occupy a water-filled pocket surrounding an nNOS-specific aspartate residue (absent in eNOS). This interaction was confirmed by mutagenesis studies, making 7-phenyl-2-aminoquinolines the first aminoquinolines to interact with this residue.
抑制神经元型一氧化氮合酶（nNOS）是治疗或预防神经退行性疾病的一种有吸引力的策略，nNOS 是一种与神经退行性疾病有关的酶。我们之前开发了几类基于 2-氨基喹啉的 nNOS 抑制剂，但这些化合物存在一些缺点，包括非靶标混杂、对人源 nNOS 的活性低，以及对 nNOS 的选择性仅略高于相关酶。在这项研究中，我们基于 7-苯基-2-氨基喹啉合成了新的 nNOS 抑制剂，并对其进行了测试，以评估其对大鼠和人源 nNOS、人源 eNOS，以及鼠源和（在某些情况下）人源 iNOS 的抑制作用。具有 -关系的氨基喹啉和带正电荷的尾部基团的化合物具有很强的活性，对人源 nNOS 的选择性高达近 900 倍，而对人源 eNOS 的选择性则较低。X 射线晶体学表明，一些化合物的氨基占据了一个充满水的口袋，该口袋围绕着 nNOS 特有的天冬氨酸残基（在 eNOS 中不存在）。通过突变研究证实了这种相互作用，使 7-苯基-2-氨基喹啉成为第一批与该残基相互作用的氨基喹啉。
