Benzodiazepine Derivatives as Potent Vasopressin V2 Receptor Antagonists for the Treatment of Autosomal Dominant Kidney Disease.

Abstract

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 V2 receptor (V2R) regulates intracellular cAMP levels in kidneys, a series of benzodiazepine derivatives were developed targeting the V2R. Among these derivatives, compound 25 exhibited potent binding affinity to the V2R (Ki = 9.0 ± 1.5 nM) and efficacious cAMP inhibition (IC50 = 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 25 in a murine model of ADPKD demonstrated a significantly improved in vivo efficacy compared with the reference compound tolvaptan. Overall, compound 25 holds therapeutic potential for the treatment of ADPKD.

• Authors: Xudong Cao, Peng Wang, Haoxing Yuan, Haoran Zhang, Yan He, Kequan Fu, Qian Fang, Hongli Liu, Limin Su, Long Yin, Pei Xu, Yuyang Xie, Xiaochun Xiong, Junqi Wang, Xu Zhu, Dong Guo
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 13 Pg. 9295-9311 (07 14 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 35579344 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antidiuretic Hormone Receptor Antagonists
• Receptors, Vasopressin
• Vasopressins
• Benzodiazepines
• Cyclic AMP

Topics

• Animals
• Antidiuretic Hormone Receptor Antagonists (pharmacology, therapeutic use)
• Benzodiazepines (metabolism, pharmacology, therapeutic use)
• Cyclic AMP (metabolism)
• Cysts (metabolism)
• Humans
• Kidney (metabolism)
• Mice
• Polycystic Kidney, Autosomal Dominant (drug therapy, metabolism)
• Receptors, Vasopressin (metabolism)
• Vasopressins (metabolism)