A Novel Pyrrole Acylsulfonamide, Compound 42, as a Dual URAT1/GLUT9 Inhibitor: Potent Urate-Lowering Efficacy, Reduced Off-Target Effects, and Promising Druggability for Hyperuricemia.

Hyperuricemia and gout remain challenging due to the limited efficacy and safety of current therapies. Herein, we report a novel pyrrole acylsulfonamide, compound 42, rationally designed via structural simplification of lead compounds E1 and ZS-24, targeting urate transporters. In acute hyperuricemia mice, compound 42 demonstrated potent urate-lowering efficacy with a decrease ratio of 88.76%, significantly superior to Lesinurad (39.02%). Mechanistically, it synergistically inhibited URAT1 (IC50 = 2.81 ± 0.40 μM) and GLUT9 (IC50 = 12.53 ± 1.33 μM), with reduced off-target activity on OAT1 (IC50 = 7.83 ± 0.70 μM vs ZS-24's 4.90 ± 0.99 μM) to mitigate potential toxicity. It displayed superior ligand efficiency (LE = 0.44 vs ZS-24's 0.41) and favorable pharmacokinetics (T1/2 = 5.55 h, F = 51.3%). In hyperuricemic nephropathy mice, compound 42 reduced serum uric acid and protected renal function without acute and subacute toxicity at high doses, supporting its promise as a candidate for hyperuricemia and gout.