Design, Synthesis, and Biological Evaluation of Novel P2X7 Receptor Antagonists for the Treatment of Septic Acute Kidney Injury

Abstract

Sepsis-associated acute kidney injury (AKI) is a serious clinical problem, without effective drugs. Abnormal activation of the purinergic P2X7 receptor (P2X7R) in septic kidneys makes its antagonist a promising therapeutic approach. Herein, a series of novel P2X7R antagonists were designed, synthesized, and structurally optimized. Based on <i>in vitro</i> potency in human/mouse P2X7R using HEK293 cells, hepatic microsomal stability, and pharmacokinetic and preliminary <i>in vivo</i> assessments, compound <b>14a</b> was identified by respective human and mouse P2X7R IC₅₀ values of 64.7 and 10.1 nM, together with favorable pharmacokinetic properties. Importantly, <b>14a</b> dose-dependently alleviated kidney dysfunction and pathological injury in both lipopolysaccharide (LPS)- and cecal ligation/perforation (CLP)-induced septic AKI mice with a good safety profile. Mechanistically, <b>14a</b> could suppress NLRP3 inflammasome activation to inhibit the expression of cleaved caspase-1, gasdermin D, IL-1β, and IL-18 in the injured kidneys of septic mice. Collectively, these results highlighted that P2X7R antagonist <b>14a</b> exerted a therapeutic potential against septic AKI.