TRPV4: A Promising Therapeutic Target Ion Channel─Discovery of Ultrapotent Selective Antagonists

TRPV4 is a polymodal, calcium-permeable channel broadly expressed and enriched in epithelia, where it integrates mechanical, osmotic, and chemical cues to regulate calcium signaling. Although TRPV4 antagonism has long been pursued therapeutically, only one antagonist has reached patients and it lacked efficacy, likely due to pharmacokinetic limitations. We describe a novel series of small-molecule TRPV4 antagonist discovered via high-throughput screening and optimized for potency, selectivity, and developability. The lead, compound 39, demonstrates favorable absorption and elimination supporting a low, predicted once-daily oral dose, with robust margins to off-target pharmacology in early safety studies. In vivo, compound 39 attenuates responses in a mechanistically relevant cough model, indicating target engagement and functional efficacy. These findings position the preclinical compound 39 as a differentiated TRPV4 antagonist with drug-like pharmacokinetics and an encouraging nonclinical safety profile.