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作为用于治疗疼痛的σ-1受体配体的吡唑并[3,4-]嘧啶。第2部分：4位环状取代基的引入。

Pyrazolo[3,4-]pyrimidines as sigma-1 receptor ligands for the treatment of pain. Part 2: Introduction of cyclic substituents in position 4.

作者信息

Díaz José Luis, Corbera Jordi, Martínez Daniel, Bordas Magda, Sicre Cristina, Pascual Rosalia, Pretel Mª José, Marín Ana Paz, Montero Ana, Dordal Albert, Alvarez Inés, Almansa Carmen

机构信息

Drug Discovery and Preclinical Development , Esteve, Baldiri Reixach, 4-8 , 08028 Barcelona , Spain . Email:

Galchimia , Cebreiro s/n 15823 O Pino A Coruña , Spain.

出版信息

Medchemcomm. 2017 Apr 20;8(6):1246-1254. doi: 10.1039/c7md00078b. eCollection 2017 Jun 1.

DOI:10.1039/c7md00078b
PMID:30108835
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6071743/
Abstract

The replacement of acylamino by cyclic substituents in the position 4 of the pyrazolo[3,4-]pyrimidine scaffold, led to highly active sigma-1 receptor (σR) ligands. Phenyl or pyrazolyl groups were the best in terms of affinity for the σR and the 4-(1-methylpyrazol-5-yl) derivative, , was the most selective. Compound is also one of the best σR ligands ever described in terms of lipophilic ligand efficiency, which translates into a good physicochemical and ADMET profile. In addition, was identified as an antagonist of the σR in view of its potent antinociceptive profile in several pain models in mice.

摘要

在吡唑并[3,4 -]嘧啶骨架的4位用环状取代基取代酰氨基，得到了高活性的σ-1受体（σR）配体。就对σR的亲和力而言，苯基或吡唑基是最佳的，而4-(1-甲基吡唑-5-基)衍生物是最具选择性的。就亲脂性配体效率而言，化合物也是有史以来描述的最佳σR配体之一，这转化为良好的物理化学和ADMET特性。此外，鉴于其在小鼠的几种疼痛模型中具有强大的抗伤害感受特性，被确定为σR的拮抗剂。

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