Discovery of Novel Bicyclic Imidazolopyridine-Containing Human Urate Transporter 1 Inhibitors as Hypouricemic Drug Candidates with Improved Efficacy and Favorable Druggability

Lesinurad is a uricosuric agent for
the treatment of hyperuricemia
associated with gout, which was found lacking in efficacy and safety.
Here, scaffold hopping and molecular hybridization were exploited
to modify all the structural components of lesinurad, and 36 novel
compounds bearing bicyclic imidazolopyridine core were obtained. In
a mouse model of acute hyperuricemia, 29 compounds demonstrated increased
serum uric acid (SUA)-reducing activity; SUA was treated with 12, 23, and 29 about fourfold lower
compared with that of lesinurad. Moreover, 23 exhibited
stronger URAT1 inhibition activity (IC50 = 1.36 μM)
than lesinurad (IC50 = 5.54 μM). Additionally, 23 showed favorable safety profiles, and no obvious acute
toxicity was observed in Kunming mice under a single dose of 1000
mg·kg–1. 23 also achieved excellent
pharmacokinetic properties with the oral bioavailability of 59.3%.
Overall, all the results indicated that 23 is a promising
drug candidate in the treatment of hyperuricemia and gout.