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 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.