Discovery of a Novel Thienopyrimidine Compound as a Urate Transporter 1 and Glucose Transporter 9 Dual Inhibitor with Improved Efficacy and Favorable Druggability

Gout and hyperuricemia are metabolic diseases characterized
with
high serum uric acid (SUA) levels that significantly impact human
health. Lesinurad, a uricosuric agent, is limited to concurrent use
with xanthine oxidase inhibitors (XOIs) in clinical practice due to
its restricted efficacy and potential nephrotoxicity. Herein, extensive
structural modifications of lesinurad were conducted through scaffold
hopping and substituent modification strategies, affording 54 novel
derivatives containing pyrimidine-fused cyclic structures. Notably,
the thienopyrimidine compound 29 demonstrated a remarkable
2-fold increase in SUA-lowering in vivo activity
compared to lesinurad, while exhibiting potent inhibitory activity
against the urate transporter 1 (URAT1, IC50 = 2.01 μM)
and glucose transporter 9 (GLUT9, IC50 = 18.21 μM).
Furthermore, it possessed a lower effective dosage of 0.5 mg/kg, favorable
safety profile without any apparent acute toxicity at doses of 1000
mg/kg, and improved pharmacokinetic properties. Overall, we have discovered
an efficacious URAT1/GLUT9 dual inhibitor for inhibiting urate reabsorption
with favorable pharmacokinetic profiles.