2. Academic Validation
  3. Discovery of a Potent, Orally Active, and Long-Lasting P2X7 Receptor Antagonist as a Preclinical Candidate for Delaying the Progression of Chronic Kidney Disease

Discovery of a Potent, Orally Active, and Long-Lasting P2X7 Receptor Antagonist as a Preclinical Candidate for Delaying the Progression of Chronic Kidney Disease

  • J Med Chem. 2024 Oct 10;67(19):17472-17496. doi: 10.1021/acs.jmedchem.4c01395.
Ruijia Zhang 1,  Kaiyue Su 1,  Letian Yang 2,  Huaichuan Duan 1,  Lei Tang 2,  Minghai Tang 1,  Min Zhao 3,  Neng Ye 4,  Xiaoying Cai 1,  Xueqin Jiang 1,  Na Li 1,  Jing Peng 1,  Xinlu Zhang 1,  Lingkai Tang 5,  Qiang Qiu 1,  Lijuan Chen 1 6,  Wenshuang Wu 7,  Jianping Hu 5,  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, Institute of Kidney Diseases, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3 Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu 610041, China.
  • 4 National Facility for Translational Medicine (Sichuan), West China Hospital of Sichuan University, Chengdu 610041, China.
  • 5 Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu 610106, China.
  • 6 Chengdu Zenitar Biomedical Technology Co., Ltd, Chengdu 610041, China.
  • 7 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: 39311818 DOI: 10.1021/acs.jmedchem.4c01395
Abstract

Chronic kidney disease (CKD) is a condition characterized by functional deterioration with sustained inflammation and progressive fibrosis of the kidneys affecting over 800 million people worldwide. The P2X7 Receptor (P2X7R) plays a key role in CKD progression. Our previous P2X7R antagonists demonstrated good efficacy for treating kidney injury but were limited by low oral exposure and short half-life, restricting their application. This study reports the optimization of P2X7R antagonists for better oral pharmacokinetics. The candidate compound 13a with the respective IC50 of 34.86 and 25.28 nM against human and murine P2X7R, administered orally at 10 mg/kg in mice, exhibits a remarkably long half-life of 161.64 h, with a high exposure of 1,163,980.55 μg·h/L. Oral administration of 13a (0.3 or 1.0 mg/kg, twice weekly) significantly reduced renal injury and fibrosis in unilateral ureteral obstruction and adenine diet-induced mice models, highlighting its potential for delaying the progression of CKD.

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