Selective GLUT9 inhibitors for hyperuricemia via intestinal mechanism

This study reports the discovery of first-in-class selective glucose transporter 9 (GLUT9) inhibitors, with lead compounds SG4 and SG7 demonstrating high potency and target specificity, as evidenced by cryo-EM structural analysis at 3.14 Å resolution revealing key binding residues (Y71, E364, C427). In vivo studies showed SG4 and SG7 significantly reduced uric acid (urate) levels, surpassing clinical benchmarks (isobavachin, lesinurad, verinurad), while exhibiting dose-dependent dual excretion pathways (urinary/fecal at 5 mg/kg, exclusively fecal at 1 mg/kg). Pharmacokinetic analysis showed limited systemic absorption (73%‒80% intestinal retention and non-absorption) and Phase II-dominated metabolism (glucuronidation 37%, sulfation 22%), with the synthetic metabolite SG4-Gluc maintaining comparable urate-lowering efficacy in vivo and improved pharmacokinetic properties. Notably, SG4 demonstrated renal protection absent in conventional URAT1 inhibitors ( e.g. , benzbromarone and lesinurad), no acute toxicity (up to 2000 mg/kg), no subacute toxicity (1000 mg/kg, 14 days) and hERG safety (at 100 μmol/L), with mechanistic validation through GLUT9-KD models confirming target specificity and intestinal urate absorption inhibition (1–10 μg/mL in isolated intestinal sac models), collectively positioning SG4 as a promising intestinally-targeted therapeutic for hyperuricemia. The first-in-class selective GLUT9 inhibitor SG4 and its metabolite SG4-gluc represent a safe and highly effective therapy for hyperuricemia, leveraging dual excretion pathways via the kidneys and intestines.