Pyridoimidazolyl Sulfonamide Compound 2 : A Superior Dual-Acting Drug Candidate with Potent URAT1 Inhibition and Anti-Inflammatory Activity for Gout Management

Abstract The management of hyperuricemia and gout remains constrained by the narrow therapeutic index of current drugs. To improve the druggability of our previously identified URAT1 inhibitor T7, we replaced its carboxylic acid with a sulfonamide group. A total of 40 novel derivatives were synthesized, among which 23 derivatives exhibited robust in vivo serum uric acid-lowering activity. Lead compound 2 (bearing a p-bromobenzenesulfonamide) exhibited potent URAT1 inhibition (IC50 = 0.19 μM) and significantly lowered serum uric acid in hyperuricemic mice (96.8% reduction) and rats (91.9% reduction). Notably, compound 2 also inhibited IL-1β activity (IC50 = 3.39 μM), which may enhance its therapeutic potential in gout by targeting disease-associated inflammation. Compound 2 demonstrated favorable pharmacokinetics (half-life: 6.3 h, oral bioavailability: 20.1%) and high safety (MTD > 1000 mg/kg). These results establish compound 2 as a promising dual-acting candidate for gout therapy.