2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Novel P2X7 Receptor Antagonists for the Treatment of Septic Acute Kidney Injury

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

  • J Med Chem. 2023 Aug 24;66(16):11365-11389. doi: 10.1021/acs.jmedchem.3c00837.
Ruijia Zhang 1,  Kaiyue Su 1,  Letian Yang 2,  Minghai Tang 1,  Min Zhao 3,  Neng Ye 1,  Xiaoying Cai 1,  Xueqin Jiang 1,  Na Li 1,  Jing Peng 1,  Xinlu Zhang 1,  Bo Wang 2,  Wenshuang Wu 4,  Liang Ma 2,  Haoyu Ye 1
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 Division of Nephrology, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3 Laboratory of Metabolomics and Drug-induced Liver Injury, Department of Gastroenterology & Hepatology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 4 Division of Thyroid Surgery, Department of General Surgery and Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
PMID: 37582195 DOI: 10.1021/acs.jmedchem.3c00837
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 in vitro potency in human/mouse P2X7R using HEK293 cells, hepatic microsomal stability, and pharmacokinetic and preliminary in vivo assessments, compound 14a was identified by respective human and mouse P2X7R IC50 values of 64.7 and 10.1 nM, together with favorable pharmacokinetic properties. Importantly, 14a 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, 14a 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 14a exerted a therapeutic potential against septic AKI.

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