Bioorg Med Chem Lett. 2026 Mar 9:130620. doi: 10.1016/j.bmcl.2026.130620. Online ahead of print.
ABSTRACT
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 (IC = 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.
PMID:41812927 | DOI:10.1016/j.bmcl.2026.130620