Acute lung injury (ALI) significantly contributes to morbidity and mortality among critically ill patients, with common causes including pneumonia, non-pulmonary sepsis, inhalation of noxious substances, severe trauma, shock, and various other factors [1]. Despite this, lung protective strategies employing mechanical ventilation are the only treatment modalities to date that have shown a survival benefit. There are no pharmacological treatments endorsed as standard care for ALI, underlining the critical need for innovative therapeutic approaches [2], [3].

The transient receptor potential vanilloid 4 (TRPV4) ion channel, a non-selective Ca2+-permeable channel, is activated by a diverse range of stimuli such as mechanical pressure, elevated temperatures, acidic conditions, and eicosanoids[4], [5]. Research on TRPV4 channels has highlighted their significant role in modulating intracellular Ca2+ homeostasis [6], [7]. The endothelium of the pulmonary circulation serves as a crucial defense mechanism, protecting lung tissue from harmful substances and circulating pathogens [8], [9]. Extensive evidence suggests that overactivation of TRPV4 channels can lead to the disruption of lung's endothelial/epithelial barrier, a critical characteristic associated with lung injury [10], [11], [12]. TRPV4 plays a crucial role in increasing the permeability of pulmonary endothelium in both cardiogenic and non-cardiogenic pulmonary edema [6], [12], [13]. Therefore, inhibiting the activity of TRPV4 channels could represent a promising therapeutic approach for treating lung edema and injury.

Over the last two decades, significant advancements have been made in the research and development of specific inhibitors targeting TRPV4 channels, as extensively documented in references [14], [15], [16]. GSK has been a prominent contributor in this field, unveiling several potent TRPV4 antagonists, including the quinoline GSK2193874, the benzimidazole GSK-BZ, the spirocarbamate GSK2798745, and the pyrrolidine GSK3527497, all noted for their substantial activity (Fig. 1) [17], [18]. Similarly, Shionogi Inc. reported the bithiazole S-19, a formidable TRPV4 antagonist [19]. Astellas has developed a series of aminothiazole antagonists, among which AS-40 stands out not only for its potent in vitro efficacy but also for its significant in vivo activity in rat models [20]. Renovis Inc. also made noteworthy contributions to this area by reporting the sulfonamide RN-9893, distinguished by its considerable inhibitory activity against TRPV4 and favorable pharmacokinetic properties (Fig. 1) [21]. Despite these developments, the clinical advancement of most of these candidate drugs has been hindered by issues related to selectivity or safety. Remarkably, only GSK2798745 has progressed to phase II clinical trials for the treatment of heart failure, demonstrating its potential as a novel therapeutic agent.

In our previous research, we demonstrated that GSK-Bz and its analogue ACY-15 (Fig. 1) with remarkable protective effects against ALI in a murine model [22]. With a continuing interest in exploring new candidates for the treatment of ALI [22], [23], [24], we aimed to find an alternative candidates with novel structure skeletons. Among the various TRPV4 antagonists studied, the sulfonamide RN9893 emerged as a promising lead compound. Its simple structural backbone offers significant potential for chemical modifications. Therefore, in this study, we focused on the structural optimization of RN9893, with the objective of discovery novel TRPV4 inhibitors for the treatment of ALI.