Design, synthesis, and evaluation of the in vitro activity of novel dual inhibitors of XOR and URAT1 containing a benzoic acid group

Xanthine oxidoreductase (XOR) and uric acid transporter 1 (URAT1) are involved in the production and reabsorption of uric acid, respectively. However, the currently available individual XOR-or URAT1-targeted drugs have limited efficacy. Thus, strategies for combining XOR inhibitors with uricosuric drugs have been developed. Previous virtual screening identified Compounds 1-5 as hits for the potential dual inhibition of XOR/URAT1. Nevertheless, in vitro experiments yielded unsatisfactory results. The first round of optimization work on those hits was performed, and two series of compounds were designed and synthesized. Compounds of the A series exerted moderate inhibitory effects on URAT1, but extremely weak inhibitory effects on XOR. Compounds of the B series exerted strong inhibitory effects on both XOR and URAT1. B-5 exhibited the greatest inhibitory activity, with similar inhibitory effects on XOR and URAT1. The half maximal inhibitory concentration (IC50) of XOR was 0.012 +/- 0.001 mu M, equivalent to that of febuxostat (IC50 = 0.010 +/- 0.001 mu M). The IC50 of URAT1 was 30.24 +/- 3.46 mu M, equivalent to that of benzbromarone (IC50 = 24.89 +/- 7.53 mu M). Through this optimization, the in vitro activity of most compounds of the A and B series against XOR and URAT1 was significantly improved versus that of the hits. Compound B-5 should be further investigated.