<br>发现 4-氨基-1,6-二氢-7H-吡咯并[2,3-d]吡吼-7-酮衍生物作为潜在的受体相互作用丝氨酸/苏氨酸蛋白激酶 1 （RIPK1）抑制剂,European Journal of Medicinal Chemistry

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发现 4-氨基-1,6-二氢-7H-吡咯并[2,3-d]吡吼-7-酮衍生物作为潜在的受体相互作用丝氨酸/苏氨酸蛋白激酶 1 （RIPK1）抑制剂
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2023-12-27 , DOI: 10.1016/j.ejmech.2023.116076
Chufeng Zhang ₁ , Yulian Chen ₁ , Yong Li ₂ , Na Shi ₁ , Yaxin Teng ₁ , Na Li ₁ , Minghai Tang ₁ , Ziyan Ma ₁ , Dexin Deng ₁ , Lijuan Chen ₃

Affiliation

受体相互作用丝氨酸/苏氨酸蛋白激酶 1 （RIPK1）是坏死性凋亡信号通路中的重要调节因子，被认为是治疗多种炎症性疾病的有吸引力的治疗靶点。在本文中，我们描述了 4-氨基-1,6-二氢-7H-吡咯洛 [2,3-d] 吡吼-7-酮衍生物作为 RIPK1 抑制剂的设计、合成和构效关系。其中，13c 显示出良好的 RIPK1 激酶抑制活性，IC50 值为 59.8 nM，与其他坏死性凋亡调节激酶相比具有高 RIPK1 结合亲和力（RIPK1 Kd = 3.5 nM，RIPK3 Kd = 1700 nM，MLKL Kd > 30,000 nM）。13c 有效阻断了 TNFα 诱导的人细胞和小鼠细胞坏死性凋亡（EC50 = 1.06–4.58 nM），并抑制了 TSZ 诱导的 RIPK1/RIPK3/MLKL 通路磷酸化。在肝脏微粒体测定研究中，13c 的清除率和 13c 半衰期分别为 18.40 mL/min/g 和 75.33 min。13c 显示出可接受的药代动力学特征，口服生物利用度为 59.55%。在 TNFα 诱导的全身炎症反应综合征中，13c 预处理可有效保护小鼠免受体温损失和死亡。总体而言，这些化合物是未来优化研究的有希望的候选化合物。

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Discovery of 4-amino-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one derivatives as potential receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitors

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an important regulatory factor in the necroptosis signaling pathway, and is considered an attractive therapeutic target for treating multiple inflammatory diseases. Herein, we describe the design, synthesis, and structure–activity relationships of 4-amino-1,6-dihydro-7H-pyrrolo [2,3-d]pyridazin-7-one derivatives as RIPK1 inhibitors. Among them, 13c showed favorable RIPK1 kinase inhibition activity with an IC50 value of 59.8 nM, and high RIPK1 binding affinity compared with other regulatory kinases of necroptosis (RIPK1 Kd = 3.5 nM, RIPK3 Kd = 1700 nM, and MLKL Kd > 30,000 nM). 13c efficiently blocked TNFα-induced necroptosis in both human and murine cells (EC50 = 1.06–4.58 nM), and inhibited TSZ-induced phosphorylation of the RIPK1/RIPK3/MLKL pathway. In liver microsomal assay studies, the clearance rate and half-life of 13c were 18.40 mL/min/g and 75.33 min, respectively. 13c displayed acceptable pharmacokinetic characteristics, with oral bioavailability of 59.55%. In TNFα-induced systemic inflammatory response syndrome, pretreatment with 13c could effectively protect mice from loss of body temperature and death. Overall, these compounds are promising candidates for future optimization studies.

更新日期：2023-12-27

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