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 (K i = 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.

PF‐06409577 inhibits renal cyst progression by concurrently inhibiting the mTOR pathway and CFTR channel activity

“…Pkd1 flox/flox ;Ksp-Cre ADPKD mice Pkd1 flox/flox ;Ksp-Cre ADPKD mice were generated as previously described [15]. In brief, Pkd1 flox/+ ;Ksp-Cre mice were self-crossed to generate wild-type (WT, Pkd1 +/+ ;Ksp-Cre) and ADPKD (Pkd1 flox/flox ;Ksp-Cre) mice [13,16].…”

Optical-Controlled Kinetic Switch: Fine-Tuning of the Residence Time of an Antagonist Binding to the Vasopressin V2 Receptor in In Vitro, Ex Vivo, and In Vivo Models of ADPKD

“…Washout experiments were also conducted by preincubating cis aLPs-5g ( cis ) or trans aLPs-5g ( trans ) at the same concentration (1 μM) with CHOhV 2 R cells for 30 min, which was followed by two consecutive washout steps irradiated with light at 365 nm to modulate the dissociation process from the receptor. The concentration-dependent experiments for trans- or cis - aLPs-5g were conducted as described previously . In all cases, the incubation was stopped by consecutively adding dye-labeled cAMP and cryptate-labeled anti-cAMP antibody in lysis buffer.…”

“…Currently, identification and optimization of V 2 R antagonists are heavily based on steady–state parameters, such as affinity. This has yielded a plethora of V 2 R antagonists with high V 2 R binding affinity. − Disappointingly, their progression toward efficacious clinical candidates remains largely unsuccessful. A recent study disclosed that the affinity of V 2 R antagonists was not correlated with their ex vivo or in vivo efficacy in inhibiting the growth of renal cysts .…”

G protein-coupled receptors in cochlea: Potential therapeutic targets for hearing loss

“…Among these GPCR-targeted drugs, V2R antagonist (OPC-41061/Tolvaptan) and AA2AR antagonist (istradefylline) have been approved by the US Food and Drug Administration (FDA) (NDA022075, NDA022275). V2R antagonist (OPC-41061/Tolvaptan) is approved for the treatment of autosomal dominant polycystic kidney disease, fibrosis, hyponatremia, heart failure, and the syndrome of dysregulated antidiuretic hormone secretion in humans ( Cao et al, 2022 ; Martin-Grace et al, 2022 ). AA2AR antagonist (istradefylline) is widely used to treat Parkinson’s disease in humans ( Merighi et al, 2022 ).…”