Cyst formation and enlargement in autosomal dominant kidney disease (ADPKD) is mainly driven by aberrantly increased cytosolic cAMP in renal tubule epithelial cells. Because the vasopressin V receptor (VR) regulates intracellular cAMP levels in kidneys, a series of benzodiazepine derivatives were developed targeting the VR. Among these derivatives, compound exhibited potent binding affinity to the VR ( = 9.0 ± 1.5 nM) and efficacious cAMP inhibition (IC = 9.2 ± 3.0 nM). This led to the suppression of cyst formation and growth in both an MDCK cell model and an embryonic kidney cyst model. Further advancing compound in a murine model of ADPKD demonstrated a significantly improved efficacy compared with the reference compound tolvaptan. Overall, compound holds therapeutic potential for the treatment of ADPKD.
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