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.

Citation

Xudong Cao, Peng Wang, Wenchao Zhao, Haoxing Yuan, Hongtao Hu, Ting Chen, Yixiao Zhang, Ying Ren, Limin Su, Kequan Fu, Hongli Liu, Dong Guo. Structure-Affinity and Structure-Kinetic Relationship Studies of Benzodiazepine Derivatives for the Development of Efficacious Vasopressin V2 Receptor Antagonists. Journal of medicinal chemistry. 2023 Mar 09;66(5):3621-3634

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PMID: 36732931

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