化学
药效团
广告
吡唑
立体化学
吗啉
化学合成
铅化合物
生物活性
胺气处理
分子模型
受体
选择性
体外
药理学
生物化学
药物化学
有机化学
医学
催化作用
作者
José Luis Dı́az,Rosa Cuberes,Joana Berrocal,Montserrat Contijoch,Ute Christmann,Ariadna Fernández,Adriana Port,Jörg Holenz,Helmut Buschmann,Christian Laggner,Maria Teresa Serafini,Javier Burgueño,Daniel Zamanillo,Manuel Merlos,José Miguel Vela,Carmen Almansa
摘要
The synthesis and pharmacological activity of a new series of 1-arylpyrazoles as potent σ1 receptor (σ1R) antagonists are reported. The new compounds were evaluated in vitro in human σ1R and guinea pig σ2 receptor (σ2R) binding assays. The nature of the pyrazole substituents was crucial for activity, and a basic amine was shown to be necessary, in accordance with known receptor pharmacophores. A wide variety of amines and spacer lengths between the amino and pyrazole groups were tolerated, but only the ethylenoxy spacer and small cyclic amines provided compounds with sufficient selectivity for σ1R vs σ2R. The most selective compounds were further profiled, and compound 28, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862), which showed high activity in the mouse capsaicin model of neurogenic pain, emerged as the most interesting candidate. In addition, compound 28 exerted dose-dependent antinociceptive effects in several neuropathic pain models. This, together with its good physicochemical, safety, and ADME properties, led compound 28 to be selected as clinical candidate.
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