Targeting Receptor-Interacting Protein Kinase 1 by Novel Benzothiazole Derivatives: Treatment of Acute Lung Injury through the Necroptosis Pathway

  • J Med Chem. 2023 Mar 12. doi: 10.1021/acs.jmedchem.3c00197.
Xinqi Zhang  1 ,  Qianyu Han  2 ,  Ruilin Hou  1 ,  Lijuan Xu  3 ,  Wannian Zhang  1  3 ,  Chengguo Xing  4 ,  Lei Xue  2 ,  Chunlin Zhuang  1  3
Affiliations
  • 1. School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China.
  • 2. Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
  • 3. School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
  • 4. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
PMID: 36908007 DOI: 10.1021/acs.jmedchem.3c00197
Abstract

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are serious and devastating pulmonary manifestations of acute systemic inflammation with high morbidity and mortality worldwide. Currently, there are no specific effective treatments for ALI/ARDS. RIPK1, which contributes to Necroptosis and inflammation, is confirmed to be a promising strategy for the treatment of ALI. Herein, 23 benzothiazole derivatives were designed to specifically target RIPK1, and SZM-1209 showed high anti-necroptotic activity (EC50 = 22.4 nM) and kinase selectivity on RIPK1 over RIPK3 (Kd,RIPK1 = 85 nM, Kd,RIPK3 > 10,000 nM). In a mTNF-α-induced systemic inflammatory response syndrome (SIRS) model, SZM-1209 could completely reverse mouse deaths with significant anti-inflammatory effects. Furthermore, in a NNK short-term intratracheal exposure-induced ALI model, SZM-1209 significantly alleviated ALI by reducing pulmonary edema and pathological damage. Collectively, activities of SZM-1209 against RIPK1, Necroptosis, SIRS, and ALI warranted further investigation of optimized benzothiazoles as promising lead structures against ALI-related diseases.

Products