Discovery of 1,2-Diol TRPV4 Antagonists with Efficacy in a 3D Myocardial Fibrosis Organoid Model and a Murine TAC Pressure-Overload Model

Cardiac fibrosis drives adverse ventricular remodeling and progression to heart failure, yet small-molecule therapies targeting mechanosensitive profibrotic signaling remain challenging. Herein, starting from our reported vicinal-diol TRPV4 antagonist AH001, we performed structure-guided optimization to generate a focused series of active analogues. A single-point TRPV4 Ca 2+ influx assay (5 μM) was used for rapid screening and SAR analysis, followed by tissue-level validation in oxygen–glucose deprivation (OGD)-induced 3D myocardial organoids. Compound 26 markedly suppressed fibrosis-associated phenotypes in this organoid model, with a phenotypic IC 50 of 6.45 μM. In vivo, compound 26 improved cardiac function and attenuated adverse remodeling in a murine transverse aortic constriction (TAC) pressure-overload model. Together, these findings support compound 26 as a promising candidate for the treatment of cardiac fibrosis.