Discovery of benzothiazole derivatives as novel orally receptor-interacting protein kinase 1 (RIPK1) inhibitors for inflammatory disease therapy.

Receptor-interacting protein kinase 1 (RIPK1), a significant node in the TNF signaling pathway, plays a critical role in modulating inflammatory cell proliferation, apoptosis, and necroptosis. Herein, we report the discovery of benzothiazole derivatives as potent RIPK1 inhibitors. Among them, compound 2q demonstrated significant anti-necroptotic activity by protecting cells against necroptosis. In addition, compound 2q exhibited excellent bioavailability and provided strong protective effects in the systemic inflammatory response syndrome (SIRS) model and humanized acute graft versus host disease (GVHD) model. Collectively, these findings indicate that 2q is a novel and promising candidate for the treatment of inflammatory diseases.