Structure–Affinity and Structure–Kinetic Relationship Studies of Benzodiazepine Derivatives for the Development of Efficacious Vasopressin V₂ Receptor Antagonists

Vasopressin V₂ receptors (V₂R) are a promising drug target for autosomal dominant polycystic kidney disease (ADPKD). As previous research demonstrated that the residence time of V₂R antagonists is critical to their efficacy in both ex vivo and in vivo models of ADPKD, we performed extensive structure–kinetic relationship (SKR) analyses on a series of benzodiazepine derivatives. We found that subtle structural modifications of the benzodiazepine derivatives dramatically changed their binding kinetics but not their affinity. Compound 18 exhibited a residence time of 77 min, which was 7.7-fold longer than that of the reference compound tolvaptan (TVP). Accordingly, compound 18 exhibited higher efficacy compared to TVP in an in vivo model of ADPKD. Overall, our study exemplifies a kinetics-directed medicinal chemistry effort for the development of efficacious V₂R antagonists. We envision that this strategy may also have general applicability in other therapeutic areas.