Exploration and Structure–activity Relationship Research of Benzenesulfonamide Derivatives As Potent TRPV4 Inhibitors for Treating Acute Lung Injury

RN -9893, a TRPV4 antagonist identified by Renovis Inc., showcased notable inhibition of TRPV4 channels. This research involved synthesizing and evaluating three series of RN -9893 analogues for their TRPV4 inhibitory efficacy. Notably, compounds 1b and 1f displayed a 2.9 to 4.5 -fold increase in inhibitory potency against TRPV4 (IC 50 = 0.71 +/- 0.21 mu M and 0.46 +/- 0.08 mu M, respectively) in vitro , in comparison to RN -9893 (IC 50 = 2.07 +/- 0.90 mu M). Both compounds also significantly outperformed RN -9893 in TRPV4 current inhibition rates (87.6 % and 83.2 % at 10 mu M, against RN-9893 ' s 49.4 %). For the first time, these RN -9893 analogues were profiled in an in vivo mouse model, where intraperitoneal injections of 1b or 1f at 10 mg/kg notably mitigated symptoms of acute lung injury induced by lipopolysaccharide (LPS). These outcomes indicate that compounds 1b and 1f are promising candidates for acute lung injury treatment.