Discovery of C2: A Novel Lead Compound for the Treatment of Gout and Hyperuricemia via Multi-Pathway Inhibition.

Abstract

Gout and hyperuricemia, prevalent metabolic disorders, are driven by elevated serum uric acid (UA) levels and subsequent monosodium urate crystal deposition, which provoke inflammatory responses and joint damage. Current therapeutic options remain unsatisfactory, underscoring the urgent need for novel agents with improved efficacy and safety profiles. In this study, we aimed to discover a new lead compound capable of concurrently addressing both hyperuricemia and associated inflammatory pain. Two novel compounds were designed and synthesized, among which C2 was identified as a promising candidate. In vitro, C2 exhibited potent dual inhibitory activity against transient receptor potential vanilloid 1 (TRPV1)-a key mediator of inflammatory pain signaling-and urate transporter 1 (URAT1), which regulated renal UA reabsorption, with IC₅₀ values of 78.52 ± 14.50 nM and 598.6 ± 115.5 nM, respectively. In vivo, oral administration of C2 (20 mg/kg) significantly reduced serum UA levels in a hyperuricemic mouse model, demonstrating efficacy comparable to dotinurad. Furthermore, in a formalin-induced inflammatory pain model, C2 produced dose-dependent antinociceptive effects. Mechanistic investigations revealed that C2 suppressed NLRP3 inflammasome activation in THP-1 cells, as indicated by reduced IL-1β secretion. Additionally, C2 ameliorated dextran sulfate sodium-induced colitis in mice, accompanied by improved histopathological scores. Collectively, these results establish C2 as a multi-target lead compound that acts simultaneously on UA transport, nociceptive signaling, and the NLRP3 inflammasome pathway, providing a strong rationale for its further development as a novel therapeutic strategy for gout and hyperuricemia.