Potent and Selective RIPK1 Inhibitors Targeting Dual‐Pockets for the Treatment of Systemic Inflammatory Response Syndrome and Sepsis

• Published in: Angewandte Chemie International Edition 2022-01, Vol.61 (5), p.e202114922-n/a
• Main Authors: Yang, Xiangbo, Lu, Huimin, Xie, Hang, Zhang, Binbin, Nie, Tianqing, Fan, Chen, Yang, Tao, Xu, Yechun, Su, Haixia, Tang, Wei, Zhou, Bing
• Format: Article
• Language: English
• Subjects: Allosteric properties; Animals; Binding studies; Drug discovery; Humans; Inflammation; Inflammatory response; Inhibitors; Kinases; Lipopolysaccharides; Lipopolysaccharides - antagonists & inhibitors; Lipopolysaccharides - pharmacology; Mice; Molecular Structure; Necroptosis; Pharmacokinetics; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; RIPK1 inhibitors; Selectivity; Sepsis; Sepsis - drug therapy; Sepsis - metabolism; Structure-Activity Relationship; Systemic inflammatory response syndrome; Systemic Inflammatory Response Syndrome - drug therapy; Systemic Inflammatory Response Syndrome - metabolism
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202114922

Sepsis, characterized with high risk of life‐threatening organ dysfunction, represents a major cause of health loss and the World Health Organization (WHO) labelled sepsis as the most urgent unmet medical need in 2017. The emerging biological understanding of the role of RIPK1 in sepsis has opened up an exciting opportunity to explore potent and selective RIPK1 inhibitors as an effective therapeutic strategy for SIRS and sepsis therapy. Herein, we have synthesized a class of highly potent dual‐mode RIPK1 inhibitors occupying both the allosteric and the ATP binding pockets, exemplified by compound 21 (ZB‐R‐55) which is about 10‐fold more potent than GSK2982772, and exhibits excellent kinase selectivity, good oral pharmacokinetics and good therapeutic effects in the LPS‐induced sepsis model, suggesting that compound ZB‐R‐55 is a highly promising preclinical candidate. A series of highly potent dual‐mode RIPK1 inhibitors occupying both the allosteric and the ATP binding pockets were developed, exemplified by compound 21 (ZB‐R‐55), which is about 10‐fold more potent than GSK2982772, and exhibits excellent kinase selectivity, good oral pharmacokinetics and good therapeutic effects in the LPS‐induced sepsis model.