Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Developmental Therapeutics, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States.
Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, California 92697-3900, United States.
J Med Chem. 2023 Jul 27;66(14):9934-9953. doi: 10.1021/acs.jmedchem.3c00782. Epub 2023 Jul 11.
A series of potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors (hnNOS), based on a difluorobenzene ring linked to a 2-aminopyridine scaffold with different functionalities at the 4-position, is reported. In our efforts to develop novel nNOS inhibitors for the treatment of neurodegenerative diseases, we discovered , which showed excellent potency toward both rat ( 15 nM) and human nNOS ( 19 nM), with 1075-fold selectivity over human eNOS and 115-fold selectivity over human iNOS. also showed excellent permeability ( = 13.7 × 10 cm s), a low efflux ratio (ER 0.48), along with good metabolic stability in mouse and human liver microsomes, with half-lives of 29 and >60 min, respectively. X-ray cocrystal structures of inhibitors bound with three NOS enzymes, namely, rat nNOS, human nNOS, and human eNOS, revealed detailed structure-activity relationships for the observed potency, selectivity, and permeability properties of the inhibitors.
报告了一系列基于二氟苯环连接到 2-氨基吡啶骨架的强效、选择性和高通透性的人神经元型一氧化氮合酶抑制剂（hnNOS），其在 4-位具有不同的官能团。在我们为开发用于治疗神经退行性疾病的新型 nNOS 抑制剂的努力中，我们发现 对大鼠（15 nM）和人 nNOS（19 nM）均具有优异的活性，对人 eNOS 的选择性为 1075 倍，对人 iNOS 的选择性为 115 倍。 还表现出优异的通透性（= 13.7 × 10 cm s）、低外排比（ER 0.48），以及在小鼠和人肝微粒体中良好的代谢稳定性，半衰期分别为 29 和>60 分钟。与三种 NOS 酶（即大鼠 nNOS、人 nNOS 和人 eNOS）结合的抑制剂的 X 射线共晶结构揭示了抑制剂的观察到的活性、选择性和通透性特性的详细结构-活性关系。
