强效,选择性和膜透的2-氨基-4-替代胺基神经氧化合成酶抑制剂
Dhananjayan Vasu1, Ha T Do1, Huiying Li2
1Department 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.
Journal of medicinal chemistry
|July 11, 2023
概括
研究人员开发了针对神经退行性疾病的神经氧化合成酶 (nNOS) 的新型抑制剂. 化合物17显示出高强度,选择性和细胞透性,显示出治疗应用的前景.
科学领域:
- 药用化学 医学化学
- 神经科学是一个神经科学.
- 药理学 药理学是指药理学的学科.
背景情况:
- 神经元氧化合成酶 (nNOS) 在神经功能中起着至关重要的作用.
- 对nNOS的失调与各种神经退行性疾病有关.
- 选择性nNOS抑制剂的开发对于治疗干预至关重要.
研究的目的:
- 设计和合成新型,强效和选择性人类nNOS (hnNOS) 抑制剂.
- 评估这些抑制剂的药理性质,包括效力,选择性,透性和代谢稳定性.
- 阐明结构-活性关系 (SAR),指导nNOS抑制剂的优化.
主要方法:
- 一系列与2-aminopyridine支架抑制剂连接的二二二环的合成.
- 在体外的酶分析以确定对老鼠nNOS,人类nNOS (hnNOS),人类内皮NOS (heNOS) 和人类可诱导NOS (hiNOS) 的抑制功效 (Ki).
- 细胞透性测试 (Pe) 和流量比 (ER) 测定.
- 使用小鼠和人类肝脏显微体进行代谢稳定性评估.
- 进行X射线晶体学,以获得与NOS酶结合的抑制剂的共晶结构.
主要成果:
- 化合物17对老鼠 (Ki = 15 nM) 和人类nNOS (Ki = 19 nM) 呈现出高强度.
- 化合物17显示出极好的选择性:比heNOS1075倍,比hiNOS115倍.
- 化合物17显示出高细胞透率 (Pe = 13.7 × 10^-6 cm s^-1) 和低排泄率 (ER = 0.48).
- 在小鼠 (t1/2 = 29 分钟) 和人类 (t1/2 > 60 分钟) 肝脏显微体中观察到良好的代谢稳定性.
- X射线结构揭示了强度,选择性和透性的详细SAR.
结论:
- 报告的二二二氨基胺衍生物代表了一类有前途的hnnos抑制剂.
- 化合物17是一种强效,选择性,高透性,代谢稳定的hnnos抑制剂.
- 这些发现为开发用于神经退行性疾病的nNOS抑制剂提供了坚实的基础.
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