Prevailing strategies directing early-phase
drug discovery heavily
rely on equilibrium-based metrics such as affinity, which overlooks
the kinetic process of a drug molecule interacting with its target.
Herein, we developed a number of vasopressin V2 receptor
(V2R) antagonists with divergent binding affinities and
kinetics for autosomal dominant polycystic kidney disease (ADPKD).
Surprisingly, the residence time of the V2R antagonists,
but not their affinity, was correlated with the efficacy in both ex vivo and in vivo models of ADPKD. We
envision that the kinetics-directed drug candidate selection and development
may have general applicability for ADPKD and other therapeutic areas
as well.
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.
Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) involves over‐proliferation of cyst‐lining epithelial cells and excessive cystic fluid secretion. While metformin effectively inhibits renal cyst growth in mouse models of ADPKD it exhibits low potency, and thus an adenosine monophosphate‐activated protein kinase (AMPK) activator with higher potency is required. Herein, we adopted a drug repurposing strategy to explore the potential of PF‐06409577, an AMPK activator for diabetic nephropathy, in cellular,
ex vivo
and
in vivo
models of ADPKD. Our results demonstrated that PF‐06409577 effectively down‐regulated mammalian target of rapamycin pathway‐mediated proliferation of cyst‐lining epithelial cells and reduced cystic fibrosis transmembrane conductance regulator‐regulated cystic fluid secretion. Overall, our data suggest that PF‐06409577 holds therapeutic potential for ADPKD treatment.
Vasopressin V 2 receptors (V 2 R) are a promising drug target for autosomal dominant polycystic kidney disease (ADPKD). As previous research demonstrated that the residence time of V 2 R 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 V 2 R antagonists. We envision that this strategy may also have general applicability in other therapeutic areas.
The pharmacological activity of a small-molecule ligand is linked to its receptor residence time. Therefore, precise control of the duration for which a ligand binds to its receptor is highly desirable. Herein, we designed photoswitchable ligands targeting the vasopressin V 2 receptor (V 2 R), a validated target for autosomal dominant polycystic kidney disease (ADPKD). We adapted the photoswitching trait of azobenzene to the parent V 2 R antagonist lixivaptan (LP) to generate azobenzene lixivaptan derivatives (aLPs). Among them, aLPs-5g was a potential optical-controlled kinetic switch. Upon irradiation, cis-aLPs-5g displayed a 4.3-fold prolonged V 2 R residence time compared to its thermally stable trans configuration. The optical-controlled kinetic variations led to distinct inhibitory effects on cellular functional readout. Furthermore, conversion of the cis/trans isomer of aLPs-5g resulted in different efficacies of inhibiting renal cystogenesis ex vivo and in vivo. Overall, aLPs-5g represents a photoswitch for precise control of ligand− receptor residence time and, consequently, the pharmacological activity.
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