Design, synthesis, and biological evaluation of pyridine-triazole derivatives as URAT1 inhibitors with potential application in hyperuricemia and gout

Hyperuricemia is a major risk factor for gout and is closely associated with metabolic and cardiovascular disorders. Urate-lowering drugs targeting the urate transporter 1 (URAT1) represent an effective therapeutic strategy; however, the clinical application of benzbromarone is limited by its hepatorenal toxicity. In this study, a series of novel pyridine-triazole derivatives were designed through a scaffold-hopping strategy based on benzbromarone, aiming to improve safety while retaining urate-lowering efficacy. Among the derivatives, analog HYJ-2 showed marginally stronger inhibition of URAT1-mediated urate transport in vitro (IC₅₀ = 368 nM) than benzbromarone. In a hyperuricemic mouse model, HYJ-2 demonstrated effective serum uric acid-lowering activity without inducing apparent hepatic or renal injury. In addition, HYJ-2 showed markedly reduced cytotoxicity toward hepatic and renal cell lines and did not significantly induce Apoptosis or mitochondrial dysfunction in hepatic cells. Computational docking suggested favorable interactions between HYJ-2 and key residues within the URAT1 binding pocket. Overall, these results identified HYJ-2 as a promising URAT1 Inhibitor with potential application in the treatment of hyperuricemia and gout.