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

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 44, 54, and 83 compared with lesinurad or benzbromarone.
In the URAT1 inhibition assay, 44 was over 8-fold more
potent than lesinurad (IC50: 1.57 μM vs 13.21 μM). Notably, 83 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 44 and 54. Compounds 44, 54, and 83 showed favorable drug-like pharmacokinetics and appear
to be promising candidates for the treatment of hyperuricemia and
gout.