Discovery of a Novel Thienopyrimidine Derivative as a Potent Dual URAT1/GLUT9 Inhibitor with Enhanced Urate-Lowering Efficacy, Superior Pharmacokinetics, and Favorable Safety Profile for Gout and Hyperuricemia.

Gout and hyperuricemia, caused by high serum uric acid, require safer and more effective treatments due to the toxicity and limited efficacy of current drugs. Dual inhibition of URAT1 and GLUT9 may reduce renal toxicity compared to single-target approaches. Starting from lead compound F-5, we used scaffold hopping and structure-guided design to develop 46 novel polycyclic pyrimidine derivatives. Among these, compound 17 showed potent and balanced inhibition of URAT1 (IC50 = 4.01 μM) and GLUT9 (IC50 = 1.60 μM), greatly improving upon F-5. Additionally, 17 reduced serum uric acid levels by 82.4% in hyperuricemic mice, while it exhibited favorable pharmacokinetic profiles in rats (F = 33.71 vs 20.13% for F-5). Significantly, 17 was efficacious at a low dose (0.5 mg/kg) and showed no acute toxicity at 1000 mg/kg. These results support 17 as a promising dual URAT1/GLUT9 inhibitor with improved efficacy, pharmacokinetics, and safety for treating gout and hyperuricemia.