Discovery of novel biaryl benzoxazepinones as dual-mode receptor-interacting protein kinase-1 (RIPK1) inhibitors

In this study, a series of novel biaryl benzoxazepinone RIPK1 inhibitors were designed and synthesized by introducing different aryl substituents at the C7 position of benzoxazepinone. As a result, p-cyanophenyl substituted analog 19 exhibited the most potent in vitro anti-necroptotic effect in HT-29 cells (EC50 = 1.7 nM) and superior protection against temperature loss and death in mice in the TZ-induced SIRS model compared to GSK'772. What's more, in vivo analysis of the levels of inflammatory factors in mice also revealed that compound 19 had better anti-inflammatory activity than GSK'772.PMID:38309200 | DOI:10.1016/j.bmc.2024.117611

Source: Bioorganic and Medicinal Chemistry - February 3, 2024 Category: Chemistry Authors: YuFeng Xin Pengcheng Dai Hongming Shao Chunlin Zhuang Jiao Li Source Type: research