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

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

  • Bioorg Med Chem. 2024 Feb 15:100:117611. doi: 10.1016/j.bmc.2024.117611.
YuFeng Xin 1 Pengcheng Dai 1 Hongming Shao 2 Chunlin Zhuang 3 Jiao Li 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China.
  • 2 School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
  • 3 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China; School of Pharmacy, Second Military Medical University, Shanghai 200433, China. Electronic address: zclnathan@163.com.
  • 4 School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai 200072, China. Electronic address: lijiao_2012@126.com.
Abstract

Systemic inflammatory response syndrome (SIRS), an exaggerated defense response of the organism to a noxious stressor, involves a massive inflammatory cascade that ultimately leads to reversible or irreversible end-organ dysfunction and even death. Suppressing RIPK1, a key protein in Necroptosis pathway, has been proven to be an effective therapeutic strategy for inflammation and SIRS. 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.

Keywords

Anti-necroptosis; Biaryl benzoxazepinone; RIPK1 inhibitor.

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