Design, Synthesis, and Biological Evaluation of TRPV4-KCa2.3 Coupling Enhancers as Novel Therapeutic Agents for Hypertension

Although current treatment strategies for hypertension are well-developed, there remains a group of patients who do not respond adequately to available medications. As a result, the identification of new therapeutic targets and the design of target-specific drugs are crucial directions for the future management of hypertension. Our previous research identified the TRPV4-KCa2.3 complex as a novel target for hypertension treatment, leading to the discovery of the positive compound JNc-440. Using JNc-440 as a lead molecule, 21 compounds were designed and synthesized across five distinct series. Among these, representative compounds IB-2 and II-9 demonstrated the ability to restore the coupling of the decoupled complex under hypertensive conditions and significantly reduced blood pressure in a high salt-induced hypertensive mouse model. This work lays a foundation for the future development of novel therapeutics targeting hypertension.