Discovery of Non-benzoazacyclic V ₂ R Antagonists for the Treatment of Autosomal Dominant Polycystic Kidney Disease

Vasopressin V₂ receptor (V₂R) is a validated therapeutic target for autosomal dominant polycystic kidney disease (ADPKD). Most reported V₂R antagonists share a benzoazacyclic scaffold with limited structural diversity. In this study, structural analysis of V₂R bound to the FDA-approved V₂R antagonist tolvaptan and a previously reported derivative (compound 18) revealed that the interaction with a hydrophobic subpocket formed by residues V206^5.39, I209^5.42, and F287^6.51 plays a critical role in antagonistic activity. Guided by this structural insight, we designed a series of non-benzoazacyclic analogs. Compound <b>29</b> (<b>XYDC2050</b>) exhibited high V₂R binding affinity (<i>K</i>_i = 2.8 ± 0.1 nM) and potent cAMP inhibition (IC₅₀ = 12.0 ± 2.0 nM). Notably, <b>XYDC2050</b> displayed 162-fold selectivity over V_1AR, surpassing that of tolvaptan (123-fold). <i>In vitro</i> and <i>in vivo</i> studies demonstrated that <b>XYDC2050</b> effectively suppressed renal cyst formation and slowed disease progression. These results support <b>XYDC2050</b> as a potential lead compound for ADPKD therapy.