鉴定融合嘧啶类化合物为白细胞介素 17 分泌抑制剂。
Identification of fused pyrimidines as interleukin 17 secretion inhibitors.
机构信息
Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491, Trondheim, Norway.
Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491, Trondheim, Norway; GlucoSet AS, Richard Birkelandsvei 2B, 7034, Trondheim, Norway.
出版信息
Eur J Med Chem. 2018 Jul 15;155:562-578. doi: 10.1016/j.ejmech.2018.06.019. Epub 2018 Jun 15.
Inhibiting the interleukin 17 pathway is of interest in a number of autoimmune diseases. Herein, 42 fused pyrimidines have been evaluated as interleukin 17 secretion inhibitors using a phenotypic assay with peripheral blood mononuclear cells. 7H-Pyrrolo [2,3-d]pyrimidin-4-amines having aryl groups at C-5 or C-6 were found more active than the corresponding thieno- and furopyrimidines. Low cytotoxicity was seen for the most active inhibitors. However, the pyrrolopyrimidines also inhibit interleukin 5 secretion, suggesting that selective interleukin 17 inhibitors should rather be based on furopyrimidines. Profiling towards a panel of 51 kinases and assays towards the retinoic acid receptor-related orphan receptor gamma were performed in order to identify the compounds mode of action.
抑制白细胞介素 17 途径在许多自身免疫性疾病中都很有意义。在此，使用外周血单核细胞的表型测定法，评估了 42 种融合嘧啶作为白细胞介素 17 分泌抑制剂。在 C-5 或 C-6 位具有芳基的 7H-吡咯并[2,3-d]嘧啶-4-胺比相应的噻吩并和呋喃嘧啶更具活性。最活跃的抑制剂的细胞毒性较低。然而，吡咯并嘧啶也抑制白细胞介素 5 的分泌，这表明选择性白细胞介素 17 抑制剂应该基于呋喃嘧啶。为了确定化合物的作用方式，对 51 种激酶进行了分析，并对维甲酸受体相关孤儿受体 γ 进行了测定。
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