Drug-likeness approach of 2-aminopyrimidines as histamine H3 receptor ligands
Drug-likeness approach of 2-aminopyrimidines as histamine H3 receptor ligands
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2-氨基嘧啶作为组胺 H3 受体配体的药物类似方法
DOI：
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发表时间：
2014
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通讯作者：
H. Stark
中科院分区：
文献类型：
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作者：
B. Sadek;A. Schreeb;J. Schwed;L. Weizel;H. Stark
合成了一系列含有 2,4-二氨基和 2,4,6-三氨基嘧啶衍生物（化合物 2-7）的化合物，并测试了与 HEK-293 细胞中稳定表达的人组胺 H3 受体 (hH3Rs) 以及与 Sf9 细胞中的 Gαi2 和 Gβ1γ2 亚基共表达的人 H4Rs (hH4Rs) 的结合亲和力。我们的构效关系研究表明，先导化合物 6-(4-甲基哌嗪-1-基)-N4-(3-(哌啶-1-基)丙基)嘧啶-2,4-二胺（化合物 1）对 hH3R 的亲和力和选择性不令人满意，我们的结构-活性关系研究表明，用 N-苄胺取代 4-甲基哌嗪并在 2-位取代胺基。具有 3-哌啶基丙氧基苯基部分作为 hH3R 药效团的 2-氨基嘧啶核心结构导致 N4-苄基-N2-(4-(3-(哌啶-1-基)丙氧基)苯基)嘧啶-2,4-二胺（化合物 5）具有高 hH3R 亲和力 (ki =4.49±1.25 nM) 和 H3R 受体亚型选择性超过6,500×。此外，基于其靶向药物相似性进行了初始度量分析，以预测量化亲脂性、配体效率、亲脂性依赖性配体效率、分子大小无关效率和拓扑分子极性表面。至于潜在的 H3R 配体的开发，结果表明，hH3R 药效团在 hH4R 亲和结构支架中的整合产生了具有高 hH3R 亲和力（4.5-650 nM）、中至低 hH4R 亲和力（4,500-30,000 nM）、受体亚型选择性（hH4R/hH3R 比率；8-6,500）的化合物，并且有希望计算出药物相似特性。
A small series of compounds containing derivatives of 2,4-diamino- and 2,4,6-triaminopyrimidine (compounds 2–7) was synthesized and tested for binding affinity to human histamine H3 receptors (hH3Rs) stably expressed in HEK-293 cells and human H4Rs (hH4Rs) co-expressed with Gαi2 and Gβ1γ2 subunits in Sf9 cells. Working in part from the lead compound 6-(4-methylpiperazin-1-yl)-N4-(3-(piperidin-1-yl)propyl)pyrimidine-2,4-diamine (compound 1) with unsatisfactory affinity and selectivity to hH3Rs, our structure-activity relationship studies revealed that replacement of 4-methylpiperazino by N-benzylamine and substitution of an amine group at the 2-position of the 2-aminopyrimidine core structure with 3-piperidinopropoxyphenyl moiety as an hH3R pharmacophore resulted in N4-benzyl-N2-(4-(3-(piperidin-1-yl)propoxy)phenyl)pyrimidine-2,4-diamine (compound 5) with high hH3R affinity (ki =4.49±1.25 nM) and H3R receptor subtype selectivity of more than 6,500×. Moreover, initial metric analyses were conducted based on their target-oriented drug-likeness for predictively quantifying lipophilicity, ligand efficiency, lipophilicity-dependent ligand efficiency, molecular size-independent efficiency, and topological molecular polar surface. As to the development of potential H3R ligands, results showed that integration of the hH3R pharmacophore in hH4R-affine structural scaffolds resulted in compounds with high hH3R affinity (4.5–650 nM), moderate to low hH4R affinity (4,500–30,000 nM), receptor subtype selectivity (ratio hH4R/hH3R; 8–6,500), and promising calculated drug-likeness properties.