Discovery of a Trifluoromethoxy Cyclopentanone Benzothiazole Receptor-Interacting Protein Kinase 1 Inhibitor as the Treatment for Alzheimer's Disease

  • J Med Chem. 2022 Nov 10;65(21):14957-14969. doi: 10.1021/acs.jmedchem.2c01478.
Yi Sun  1 ,  Lijuan Xu  2  3 ,  Hongming Shao  3 ,  Danni Quan  2 ,  Zixin Mo  1 ,  Jue Wang  1 ,  Wannian Zhang  2  3 ,  Jianqiang Yu  2 ,  Chunlin Zhuang  2  3 ,  Ke Xu  4  5
Affiliations
  • 1. Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 2. School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China.
  • 3. School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
  • 4. Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.
  • 5. Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai 200434, China.
PMID: 36288088 DOI: 10.1021/acs.jmedchem.2c01478
Abstract

Receptor-interacting protein kinase 1 (RIPK1) contributes to a broad set of inflammations and Necroptosis in human diseases, which also plays an important role in the pathogenesis of Alzheimer's disease (AD). The inhibition of RIPK1 could be a novel strategy to improve cognitive function. SZM679, a highly specific RIPK1 Inhibitor (Kd,RIPK1 = 8.6 nM, Kd,RIPK3 > 5000 nM), was developed by our group with superior high antinecroptotic activity (EC50 = 2 nM), and investigated to completely reverse the tumor necrosis factor-induced systemic inflammatory response syndrome. In a streptozocin-induced AD-like mouse model, behavioral tests showed that SZM679 apparently ameliorated learning and memory dysfunction. Nissl staining revealed that SZM679 improved neuronal loss. Moreover, the Tau hyperphosphorylation, neuroinflammation, and the RIPK1 phosphorylation level in the hippocampus and cortex were significantly decreased in the SZM679-treated group. Collectively, SZM679 represents a promising lead structure for the discovery of novel RIPK1 inhibitory anti-AD agents.

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