Novel Human Urate Transporter 1 Inhibitors as Hypouricemic Drug Candidates with Favorable Druggability

Abstract

Lesinurad, a human urate transporter 1 (URAT1) inhibitor approved as a medication for the treatment of hyperuricemia associated with gout in 2015, can cause liver and renal toxicity. Here, we modified all three structural components of lesinurad by applying scaffold hopping, bioisosterism, and substituent-decorating strategies. In a mouse model of acute hyperuricemia, 21 of the synthesized compounds showed increased serum uric acid (SUA)-reducing activity; SUA was about 4-fold lower in animals treated with <b>44</b>, <b>54</b>, and <b>83</b> compared with lesinurad or benzbromarone. In the URAT1 inhibition assay, <b>44</b> was over 8-fold more potent than lesinurad (IC₅₀: 1.57 μM <i>vs</i> 13.21 μM). Notably, <b>83</b> also displayed potent inhibitory activity (IC₅₀ = 31.73 μM) against GLUT9. Furthermore, we also preliminarily explored the effect of chirality on the potency of the promising derivatives <b>44</b> and <b>54</b>. Compounds <b>44</b>, <b>54</b>, and <b>83</b> showed favorable drug-like pharmacokinetics and appear to be promising candidates for the treatment of hyperuricemia and gout.