URAT1/GLUT9-IN-1 (compound 29) effectively inhibits urate transporter 1 (URAT1) with an IC50 value of 2.01 μM and glucose transporter 9 (GLUT9) with an IC50 of 18.21 μM. This compound exhibits favorable pharmacokinetic properties and oral bioavailability, making it useful for research in gout and hyperuricemia.

GLUT9:18.21 μM

URAT1/GLUT9-IN-1 exhibits the most potent inhibition of URAT1-mediated [14C]-urate uptake, with an IC50 of 2.01 μM, making it approximately three times more effective than Lesinurad (IC50 = 5.54 μM). At a concentration of 5 μM, URAT1/GLUT9-IN-1's in vitro inhibitory activity on GLUT9 slightly surpasses that of Benzbromarone, with an IC50 of 18.21±1.03 μM. At 10 μM, its inhibition rate on XOD is less than 20%, suggesting negligible inhibitory effects. Furthermore, URAT1/GLUT9-IN-1 demonstrates inhibition of CYP enzymes, specifically CYP2C9 (IC50 = 2.00 μM) and CYP2C19 (IC50 = 5.93 μM), indicating a low potential for hepatotoxicity.

URAT1/GLUT9-IN-1, administered orally at doses of 0.25, 0.5, and 1 mg/kg, demonstrates an effective minimum dose of approximately 0.5 mg/kg for reducing serum uric acid (SUA) in an acute hyperuricemia mouse model. At a dose of 2 mg/kg, URAT1/GLUT9-IN-1 exhibits significant potential as a SUA-lowering drug, showing about 1.8 times the efficacy of Lesinurad in a stable hyperuricemia rat model. Furthermore, URAT1/GLUT9-IN-1, given orally at 100 mg/kg every other day for 14 days, shows notable safety improvements over Lesinurad in chronic hyperuricemia mice. Pharmacokinetic analysis in SD rats revealed that, at a 2 mg/kg oral dose, the compound has an AUC 0-t of 1813.4 ng•h/mL, an AUC 0-INF of 7929.1 ng•h/mL, MRT 0-INF of 2.5 hours, T 1/2 of 1.8 hours, T max of 0.25 hours, C max of 1272.7 ng/mL, and an oral bioavailability of 20.1%. For intravenous administration at the same dose, AUC 0-t is 1903.7 ng•h/mL, AUC 0-INF is 1922.9 ng•h/mL, MRT 0-INF is 0.5 hours, T 1/2 is 1.6 hours, T max is 0.083 hours, C max is 6591.8 ng/mL, and the clearance is 17.5 L•h/kg.