Design, synthesis and anti-inflammatory evaluation of novel pyrrolo [2,3-d] pyrimidin derivatives as potent JAK inhibitors
Design, synthesis and anti-inflammatory evaluation of novel pyrrolo [2,3-d] pyrimidin derivatives as potent JAK inhibitors
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DOI：
10.1016/j.bmc.2019.07.037
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发表时间：
2019-09-15
影响因子：
3.5
通讯作者：
Zhai, Xin
中科院分区：
文献类型：
--
作者：
Jiang, Feng;Zang, Linghe;Zhai, Xin
为了开发有效的JAK抑制剂，设计并合成了两个系列的4-（1H-吡唑-4-基）-7H-吡咯并[2，3-d]嘧啶衍生物（8a-8 p和11 a-11 i），它们通过将不同的N-酰基哌啶基序与baricitinib结合而成。基于酶和细胞测定的药理学结果鉴定了优化的化合物11 e，其对JAK 1和JAK 2的抑制率超过90%，并且通过抑制LPS诱导的RAW 264. 7巨噬细胞的NO生成而显示出优于baricitinib的最引人注目的抗炎功效上级。重要的是，11 e对正常RAW 264.7细胞的IC 50值为88.2 μ M，显示了低细胞毒性。11 e与JAK 1和JAK 2的结合方式与SARs分析结果雅阁。此外，细胞形态学观察和western blot分析揭示了11 e通过显著下调LPS诱导的JAK 1、JAK 2以及前细胞因子IL-1 β的高表达来减轻细胞炎症损伤的能力。总之，11 e被证实是JAK抑制剂治疗炎症性疾病的有前途的先导化合物。
Aiming to develop potent JAK inhibitors, two series of 4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives (8a-8p and 11 a-11i) were designed and synthesized by coalescing various N-acylpiperidine motifs with baricitinib. The pharmacological results based on enzymatic and cellular assays identified the optimized compound 11e, which exerted over 90% inhibition rates against JAK1 and JAK2, and displayed the most compelling anti-inflammatory efficacy superior to baricitinib by inhibiting NO generation from LPS-induced RAW264.7 macrophages. Importantly, low cytotoxity of 11e was revealed by the IC50 value of 88.2 mu M against normal RAW264.7 cells. The binding mode of 11e with JAK1 and JAK2 identified the essential structural bases in accord with SARs analysis. Furthermore, cellular morphology observation and western blot analysis disclosed the ability of 11e to relieve cells inflammatory damage by significantly down-regulating LPS-induced high expression of JAK1, JAK2, as well as pro cytokine IL-1 beta. Together, 11e was verified as a promising lead for JAK inhibitors for the treatment of inflammatory diseases.