Design, synthesis, and biological evaluation of non-conjugated Biaryl amide URAT1 inhibitors as potent Uricosuric agents.

Hyperuricemia is a major pathogenic factor for gout and is closely associated with chronic kidney disease, cardiovascular disorders, and metabolic syndrome. Although urate transporter 1 (URAT1) inhibitors effectively lower serum urate by blocking renal urate reabsorption, their clinical application remains limited by safety liabilities. Herein, we described a mechanism-guided scaffold-hopping strategy to develop safer and more effective URAT1 inhibitors by replacing the hepatotoxic conjugated diaryl ketone pharmacophore of benzbromarone (BBR) with a non-conjugated biaryl amide scaffold. Four classes of non-conjugated biaryl amides were designed, synthesized, and systematically optimized. Structure-activity relationship studies identified L22, featuring a benzothiazolone moiety, as the lead compound, exhibiting potent inhibition of URAT1-mediated urate transport (IC50 = 0.22 μM). L22 showed potent urate-lowering efficacy in both acute and chronic hyperuricemia mouse models and demonstrated superior in vivo activity to BBR. Furthermore, L22 displayed favorable pharmacokinetic properties with adequate oral exposure. Molecular docking provided a plausible structural basis for its potent URAT1 inhibitory activity. Overall, this study identified a novel non-conjugated biaryl amide scaffold for URAT1 inhibition and established L22 as a promising lead compound for further development of novel uricosuric agents.