Benzodiazepine Derivatives as Potent Vasopressin V 2 Receptor Antagonists for the Treatment of Autosomal Dominant Kidney Disease.
Journal of medicinal chemistry(2022)
摘要
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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