1. Academic Validation
  2. Investigation on the chemical space of the substituted triazole thio-benzoxazepinone RIPK1 inhibitors

Investigation on the chemical space of the substituted triazole thio-benzoxazepinone RIPK1 inhibitors

  • Eur J Med Chem. 2022 Jun 5;236:114345. doi: 10.1016/j.ejmech.2022.114345.
Yanan Hao 1 Hongming Shao 2 Zhuo Qu 1 Jiao Li 3 Ying Shi 1 Wannian Zhang 4 Jianqiang Yu 1 Peng Fu 5 Chunlin Zhuang 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China.
  • 2 School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
  • 3 Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
  • 4 School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China; School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
  • 5 Department of Pharmacy, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China. Electronic address: fucaofan@163.com.
  • 6 School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China; School of Pharmacy, Second Military Medical University, Shanghai, 200433, China. Electronic address: zclnathan@163.com.
Abstract

As a key upstream kinase involved in the activation of Necroptosis, receptor-interacting protein kinase 1 (RIPK1) plays a vital role in the treatment of relevant inflammatory diseases. Recently, we described the thio-benzoxazepinones as RIPK1 Necroptosis inhibitors. On this basis, we further explored the chemical space of the thio-benzoxazepinones by introducing substitutions on the triazole group and evaluated their anti-necroptotic activity. The structure-activity relationship (SAR) was extended for this series of new derivatives. The best compound 2 with methyl and compound 10 with fluoroethyl were obtained and both specifically inhibited Necroptosis rather than Apoptosis with EC50 values of 2.5 and 8.9 nM, respectively. They blocked the downstream necroptotic pathway to prevent Cell Lysis and prevent in vivo inflammation in a dose-dependent manner. This work provides that substituted thio-benzoxazepines can better occupy the hydrophobic cavity and enhance the hydrophobic interaction as promising lead compounds to enhance the in vivo activity of this class of compounds.

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