TY - JOUR
T1 - Discovery of 1,2-Diol TRPV4 Antagonists with Efficacy in a 3D Myocardial Fibrosis Organoid Model and a Murine TAC Pressure-Overload Model
AU - Chen, Na
AU - Sun, Ying
AU - Zhang, Tingting
AU - Yuan, Zhen
AU - Liu, Xiangning
AU - Meng, Lingwei
AU - Geng, Xiaoju
AU - Mei, Wenyi
AU - Zhao, Zhenjiang
AU - Liu, Qian
AU - Li, Yunlin
AU - Yuan, Binhua
AU - Li, Xiang
AU - He, Huan
AU - Li, Honglin
AU - Li, Chun
N1 - Publisher Copyright:
© 2026 American Chemical Society
PY - 2026/5/28
Y1 - 2026/5/28
N2 - 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 Ca2+ 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 IC50 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.
AB - 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 Ca2+ 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 IC50 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.
UR - https://www.scopus.com/pages/publications/105040674333
U2 - 10.1021/acs.jmedchem.6c00543
DO - 10.1021/acs.jmedchem.6c00543
M3 - 文章
C2 - 42132934
AN - SCOPUS:105040674333
SN - 0022-2623
VL - 69
SP - 12565
EP - 12582
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 10
ER -