Design, synthesis, and structure-activity relationship of novel RIPK2 inhibitors

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 (Kd = 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.

Automated summary

The NOD1/2 signaling pathways play important roles in immune control and host defense, and dysfunction may lead to autoimmune disorders. This study revealed the design, synthesis, and pharmacological studies of RIPK2 inhibitors, with lead compound 17 showing high affinity for RIPK2 and inhibitory effects on its kinase function.