当前位置：
X-MOL 学术
›
J. Med. Chem.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-04-19 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00259 Maris A. Cinelli 1 , Huiying Li 2 , Georges Chreifi 2 , Thomas L. Poulos 2 , Richard B. Silverman 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-04-19 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00259 Maris A. Cinelli 1 , Huiying Li 2 , Georges Chreifi 2 , Thomas L. Poulos 2 , Richard B. Silverman 1
Affiliation
|
Neuronal nitric oxide synthase (nNOS) inhibition is a promising strategy to treat neurodegenerative disorders, but the development of nNOS inhibitors is often hindered by poor pharmacokinetics. We previously developed a class of membrane-permeable 2-aminoquinoline inhibitors and later rearranged the scaffold to decrease off-target binding. However, the resulting compounds had decreased permeability, low human nNOS activity, and low selectivity versus human eNOS. In this study, 5-substituted phenyl ether-linked aminoquinolines and derivatives were synthesized and assayed against purified NOS isoforms. 5-Cyano compounds are especially potent and selective rat and human nNOS inhibitors. Activity and selectivity are mediated by the binding of the cyano group to a new auxiliary pocket in nNOS. Potency was enhanced by methylation of the quinoline and by introduction of simple chiral moieties, resulting in a combination of hydrophobic and auxiliary pocket effects that yielded high (∼500-fold) n/e selectivity. Importantly, the Caco-2 assay also revealed improved membrane permeability over previous compounds.
中文翻译：
孔中的腈：神经元一氧化氮合酶中一个小的辅助口袋的发现，导致有效和选择性的2-氨基喹啉抑制剂的发展。
抑制神经元一氧化氮合酶（nNOS）是治疗神经退行性疾病的一种有前途的策略，但是不良的药代动力学通常会阻碍nNOS抑制剂的发展。我们先前开发了一类可透过膜的2-氨基喹啉抑制剂，后来重新排列了支架以减少脱靶结合。但是，与人eNOS相比，所得化合物的通透性降低，人nNOS活性低，选择性低。在这项研究中，合成了5-取代的苯基醚连接的氨基喹啉及其衍生物，并针对纯化的NOS同工型进行了分析。5-氰基化合物是特别有效的和选择性的大鼠和人类nNOS抑制剂。活性和选择性是由氰基与nNOS中新的辅助口袋的结合所介导的。通过喹啉的甲基化和引入简单的手性部分可增强效价，从而产生疏水和辅助口袋效应的组合，从而产生高（约500倍）n / e选择性。重要的是，Caco-2分析还显示了比先前化合物更高的膜通透性。
更新日期：2017-04-19
中文翻译：
孔中的腈：神经元一氧化氮合酶中一个小的辅助口袋的发现，导致有效和选择性的2-氨基喹啉抑制剂的发展。
抑制神经元一氧化氮合酶（nNOS）是治疗神经退行性疾病的一种有前途的策略，但是不良的药代动力学通常会阻碍nNOS抑制剂的发展。我们先前开发了一类可透过膜的2-氨基喹啉抑制剂，后来重新排列了支架以减少脱靶结合。但是，与人eNOS相比，所得化合物的通透性降低，人nNOS活性低，选择性低。在这项研究中，合成了5-取代的苯基醚连接的氨基喹啉及其衍生物，并针对纯化的NOS同工型进行了分析。5-氰基化合物是特别有效的和选择性的大鼠和人类nNOS抑制剂。活性和选择性是由氰基与nNOS中新的辅助口袋的结合所介导的。通过喹啉的甲基化和引入简单的手性部分可增强效价，从而产生疏水和辅助口袋效应的组合，从而产生高（约500倍）n / e选择性。重要的是，Caco-2分析还显示了比先前化合物更高的膜通透性。
京公网安备 11010802027423号