SAR-Guided Scaffold Innovation of Selective V₂R Antagonists: Therapeutic Frontiers in ADPKD

The vasopressin V₂ receptor (V₂R) is a class A G protein-coupled receptor (GPCR) that plays a pivotal role in the regulation of renal water homeostasis and has been implicated in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) through sustained activation of cyclic adenosine monophosphate (cAMP) signaling. Pharmacological antagonism of V₂R has emerged as a clinically validated strategy for attenuating cyst growth. However, the therapeutic application of currently available V₂R antagonists remains constrained by safety liability and a relatively narrow chemical space. A recent study employed systematic structure-activity relationship (SAR) analyses to expand existing design paradigms for V₂R antagonists, leading to the identification and synthesis of a series of structurally diverse V₂R antagonist analogues. Supported by multidimensional pharmacological evaluations, these findings provide an important framework for the rational design and optimization of next-generation therapeutics for ADPKD.