提高神经元型一氧化氮合酶抑制剂生物利用度的最新进展。
Recent advances toward improving the bioavailability of neuronal nitric oxide synthase inhibitors.
机构信息
Department of Chemistry, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA.
出版信息
Curr Top Med Chem. 2013;13(7):803-12. doi: 10.2174/1568026611313070003.
Abstract
Overproduction of nitric oxide by neuronal nitric oxide synthase (nNOS) has been highly correlated with numerous neurodegenerative diseases and stroke. Given its role in human diseases, nNOS is an important target for therapy that deserves further attention. During the last decade, a large number of organic scaffolds have been investigated to develop selective nNOS inhibitors, resulting in two principal classes of compounds, 2-aminopyridines and thiophene-2- carboximidamides. The former compounds were investigated in detail by our group, exhibiting great potency and excellent selectivity; however, they suffer from poor bioavailability, which hampers their therapeutic potential. Here we present a review of various strategies adopted by our group to improve the bioavailability of 2-aminopyridine derivatives and describe recent advances in thiophene-2-carboximidamide based nNOS-selective inhibitors, which exhibit promising pharmacological profiles.
摘要
神经元型一氧化氮合酶（nNOS）产生的一氧化氮过多与许多神经退行性疾病和中风高度相关。鉴于其在人类疾病中的作用，nNOS 是治疗的一个重要靶点，值得进一步关注。在过去的十年中，已经研究了大量的有机支架来开发选择性的 nNOS 抑制剂，从而产生了两类主要的化合物，2-氨基吡啶和噻吩-2-羧基脒。我们小组详细研究了前一类化合物，它们表现出很强的效力和极好的选择性；然而，它们的生物利用度很差，这限制了它们的治疗潜力。在这里，我们回顾了我们小组为提高 2-氨基吡啶衍生物的生物利用度而采用的各种策略，并描述了基于噻吩-2-羧基脒的 nNOS 选择性抑制剂的最新进展，这些抑制剂表现出有希望的药理学特性。
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