Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Developmental Therapeutics, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, United States.
Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, CA 92697-3900, United States.
Bioorg Med Chem. 2022 Sep 1;69:116878. doi: 10.1016/j.bmc.2022.116878. Epub 2022 Jun 11.
A series of potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors (hnNOS) based on the 2-aminopyridine scaffold with a shortened amino sidechain is reported. A rapid and simple protocol was developed to access these inhibitors in excellent yields. Neuronal nitric oxide synthase (nNOS) is a novel therapeutic target for the treatment of various neurological disorders. The major challenges in designing nNOS inhibitors in humans focus on potency, selectivity over other isoforms of nitric oxide synthases (NOSs), and blood-brain barrier permeability. In this context, we discovered a promising inhibitor, 6-(3-(4,4-difluoropiperidin-1-yl)propyl)-4-methylpyridin-2-amine dihydrochloride, that exhibits excellent potency for rat (K = 46 nM) and human nNOS (K = 48 nM), respectively, with 388-fold human eNOS and 135-fold human iNOS selectivity. It also displayed excellent permeability (P = 17.3 × 10 cm s) through a parallel artificial membrane permeability assay, a model for blood-brain permeability. We found that increasing lipophilicity by incorporation of fluorine atoms on the backbone of the inhibitors significantly increased potential blood-brain barrier permeability. In addition to measuring potency, isoform selectivity, and permeability of NOS inhibitors, we also explored structure-activity relationships via structures of key inhibitors complexed to various isoforms of nitric oxide synthases.
报告了一系列基于 2-氨基吡啶骨架且具有缩短的氨基侧链的强效、选择性和高通透性的人神经元型一氧化氮合酶抑制剂（hnNOS）。开发了一种快速而简单的方案来以优异的产率获得这些抑制剂。神经元型一氧化氮合酶（nNOS）是治疗各种神经紊乱的新的治疗靶标。在人类中设计 nNOS 抑制剂的主要挑战在于效力、相对于其他一氧化氮合酶（NOS）同工型的选择性以及血脑屏障通透性。在这种情况下，我们发现了一种有前途的抑制剂，即 6-(3-(4,4-二氟哌啶-1-基)丙基)-4-甲基吡啶-2-胺二盐酸盐，它分别对大鼠（K = 46 nM）和人 nNOS（K = 48 nM）具有优异的效力，对人 eNOS 和人 iNOS 的选择性分别为 388 倍和 135 倍。它还通过平行人工膜通透性测定（一种血脑通透性模型）显示出优异的通透性（P = 17.3 × 10 cm s）。我们发现，通过在抑制剂的骨架上引入氟原子来增加亲脂性，显著提高了潜在的血脑屏障通透性。除了测量 NOS 抑制剂的效力、同工型选择性和通透性外，我们还通过与各种一氧化氮合酶同工型结合的关键抑制剂的结构探索了构效关系。
