2. Academic Validation
  3. Scaffold hopping derived novel benzoxazepinone receptor-interacting protein kinase 1 (RIP1) inhibitors as anti-necroptosis agents: Anti-inflammatory effect in systemic inflammatory response syndrome (SIRS) and epilepsy

Scaffold hopping derived novel benzoxazepinone receptor-interacting protein kinase 1 (RIP1) inhibitors as anti-necroptosis agents: Anti-inflammatory effect in systemic inflammatory response syndrome (SIRS) and epilepsy

  • Eur J Med Chem. 2024 Mar 9:269:116304. doi: 10.1016/j.ejmech.2024.116304.
Ruiqi Jiang 1,  Bin Xu 1,  Shumeng Zhi 1,  Lei Sun 1,  Baocong Yu 2,  Qing Huang 3,  Ying Shi 4
Affiliations

Affiliations

  • 1 Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area (Ningxia Medical University), Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China.
  • 2 Ningxia Key Laboratory of Craniocerebral Diseases, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China. Electronic address: ybaocong@Outlook.com.
  • 3 Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area (Ningxia Medical University), Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China. Electronic address: hq82@163.com.
  • 4 Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area (Ningxia Medical University), Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China. Electronic address: nxshiying@163.com.
PMID: 38484677 DOI: 10.1016/j.ejmech.2024.116304
Abstract

Necroptosis is a type of regulated cell death known for its pro-inflammatory nature due to the substantial release of cellular contents. The phosphorylation of key proteins, namely RIP1, RIP3, and Mixed Lineage Kinase domain-like protein (MLKL), plays a pivotal role in the processes associated with Necroptosis. Consequently, inhibiting the phosphorylation of any of these three key protein kinases could effectively block Necroptosis. Utilizing a scaffold hopping strategy, we have successfully designed and synthesized a series of novel RIP1 inhibitors with selective and anti-necrotic properties, using compound o1 as the lead compound. In comparison to o1, SY1 has demonstrated heightened antinecroptosis activity and binding affinity in vitro studies. Moreover, SY1 has exhibited superior efficacy in both in vivo studies, specifically in the context of SIRS, and pharmacokinetic assessments. Furthermore, SY1 has proven effective in significantly suppressing the central inflammatory response induced by epilepsy.

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