The NOD1/2 (nucleotide-binding oligomerization domain-containing protein 1/2) signaling pathways are involved in innate immune control and host defense. NOD dysfunction can result in a variety of autoimmune disorders. NOD-induced generation of inflammatory cytokines is mediated by receptor-interacting protein kinase 2 (RIPK2), which has been considered as a promising therapeutic target. Herein, we disclose the design, synthesis, and SAR study of a series of RIPK2 inhibitors. The lead compound 17 displayed a high affinity for RIPK2 (K_d = 5.9 nM) and was capable of inhibiting RIPK2 kinase function in an ADP-Glo assay. In vitro DMPK studies showed that compound 17 had good metabolic stability and no CYP inhibition. Compound 17 effectively suppressed inflammatory cytokine production in both cells and animal model.

NOD1/2（含有核苷酸结合寡聚结构域的蛋白质 1/2）信号通路参与先天免疫控制和宿主防御。NOD功能障碍可导致多种自身免疫性疾病。NOD 诱导的炎性细胞因子的产生是由受体相互作用蛋白激酶 2 (RIPK2) 介导的，RIPK2 被认为是一种有前途的治疗靶点。在此，我们公开了一系列 RIPK2 抑制剂的设计、合成和 SAR 研究。先导化合物17对 RIPK2 显示出高亲和力（K _d  = 5.9 nM），并且能够在 ADP-Glo​​ 测定中抑制 RIPK2 激酶功能。体外 DMPK 研究表明，化合物17具有良好的代谢稳定性，并且没有 CYP 抑制作用。化合物17有效抑制细胞和动物模型中炎性细胞因子的产生。