Identification and characterization of a potent and selective inhibitor of human urate transporter 1.

BACKGROUND: Selective inhibitors of human urate transporter 1 (hURAT1) are considered to be effective treatment for hyperuricemia and gout, which can reduce the reabsorption of more than 90% of uric acid in the proximal tubule of the kidney. We aimed to design and synthesize a more potent hURAT1 based on the structure of Lesinurad (LU), which was reported to lower uric acid levels with IC50 value of hURAT1 (about 60μM).

METHODS: A cell model was conducted and characterized via Real-time qRCR and Western blot. We synthesized and identified a new midazole analogue of LU. Cells stably-expressing hURAT1 or human organic anion transporter 1 (hOAT1) were used in the [14 C] urate or 6-carboxyfluorescein (6-CF) uptake assays to test the activities of the newly synthesized compound. The uric acid lowering effects of LU and LUM and their effects on urea nitrogen and creatinine in potassium oxonate-induced hyperuricemic rats were analyzed.

RESULTS: The [14 C] Urate uptake assay using hURAT1 stably transfected MDCK cells indicated that LUM was more potent than LU against hURAT1, with IC50 values of 3.22μM and 65.47μM, respectively. LU and LUM also effectively suppressed hOAT1-mediated 6-CF uptake, and the IC50 hURAT1/IC50 hOAT1 of LU and LUM was1.49 and 0.35 respectively, indicating a better selectivity for LUM than LU. In vivo, LUM-Na (40mg/kg) showed more potent activity in reducing serum uric acid levels in potassium oxonate-induced hyperuricemic rats, compared to similar doses of LU-Na.

CONCLUSION: LUM was demonstrated to be as potent a uricosuric drug as LU.