Discovery of a Potent, Orally Active, and Long-Lasting P2X7 Receptor Antagonist as a Preclinical Candidate for Delaying the Progression of Chronic Kidney Disease
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 <b>13a</b> with the respective IC<sub>50</sub> 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 <b>13a</b> (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.
Authors
- Haoyu Ye (ORCID: https://orcid.org/0000-0002-9185-1040)
- Liang Ma (ORCID: https://orcid.org/0000-0001-8327-7969)
- Neng Ye (ORCID: https://orcid.org/0000-0002-6605-826X)
- Xinlu Zhang (ORCID: https://orcid.org/0000-0001-7668-091X)
- Xiaoying Cai (ORCID: https://orcid.org/0000-0002-9650-0063)
- Minghai Tang (ORCID: https://orcid.org/0000-0002-5527-4223)
- T. T. Lei (ORCID: https://orcid.org/0000-0001-6324-2101)
- Na Li (ORCID: https://orcid.org/0009-0002-0688-1104)
- Kaiyue Su
- Lingkai Tang (ORCID: https://orcid.org/0000-0001-9861-7436)
- Huaichuan Duan (ORCID: https://orcid.org/0000-0001-6065-3829)
- Jianping Hu (ORCID: https://orcid.org/0000-0001-7367-3968)
- Qiang Qiu
- Wenshuang Wu (ORCID: https://orcid.org/0000-0002-1210-4865)
- Min Zhao (ORCID: https://orcid.org/0000-0001-5186-3525)
- Lijuan Chen (ORCID: https://orcid.org/0000-0002-8076-163X)
- Xueqin Jiang (ORCID: https://orcid.org/0009-0007-3137-6536)
- Ruijia Zhang (ORCID: https://orcid.org/0009-0006-8174-618X)
- Letian Yang
- Jing Peng
Institutions
- Sichuan University (CN)
- West China Hospital of Sichuan University (CN)
- Chengdu University (CN)
- State Key Laboratory of Biotherapy
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-09-23
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01395
- Citations
- 3
- Primary Topic
- Adenosine and Purinergic Signaling
- Type
- article
- Field-Weighted Citation Impact
- 1.21
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Department of Science and Technology of Sichuan Province
- West China Hospital, Sichuan University