Discovery of\na Potent, Orally Active, and Long-Lasting\nP2X7 Receptor Antagonist as a Preclinical Candidate for Delaying the\nProgression of Chronic Kidney Disease

Chronic kidney disease (CKD) is a condition characterized\nby functional\ndeterioration with sustained inflammation and progressive fibrosis\nof the kidneys affecting over 800 million people worldwide. The P2X7\nreceptor (P2X7R) plays a key role in CKD progression. Our previous\nP2X7R antagonists demonstrated good efficacy for treating kidney injury\nbut were limited by low oral exposure and short half-life, restricting\ntheir application. This study reports the optimization of P2X7R antagonists\nfor better oral pharmacokinetics. The candidate compound <b>13a</b> with the respective IC<sub>50</sub> of 34.86 and 25.28 nM against\nhuman and murine P2X7R, administered orally at 10 mg/kg in mice, exhibits\na remarkably long half-life of 161.64 h, with a high exposure of 1,163,980.55\nμg·h/L. Oral administration of <b>13a</b> (0.3 or\n1.0 mg/kg, twice weekly) significantly reduced renal injury and fibrosis\nin unilateral ureteral obstruction and adenine diet-induced mice models,\nhighlighting its potential for delaying the progression of CKD.