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

Abstract 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.