Background: Gout is the most common inflammatory arthritis, which, if left untreated or
inadequately treated, will lead to joint destruction, bone erosion and disability due to the crystal
deposition. Uric acid transporter 1 (URAT1) was the promising therapeutic target for urate-lowering
Objective: The goal of this work is to understand the structure-activity relationship (SAR) of a potent
lesinurad-based hit, sodium 2-((5-bromo-4-((4-cyclopropyl-naphth-1-yl)methyl)-4H-1,2,4-triazol-3-
yl)thio)acetate (1c), and based on that discover a more potent URAT1 inhibitor.
Methods: The SAR of 1c was systematically explored and the in vitro URAT1 inhibitory activity of
synthesized compounds 1a-1t was determined by the inhibition of URAT1-mediated [8-14C]uric acid
uptake by human embryonic kidney 293 (HEK293) cells stably expressing human URAT1.
Results: Twenty compounds 1a-1t were synthesized. SAR analysis was performed. Two highly active
URAT1 inhibitors, sodium 2-((5-bromo-4-((4-n-propylnaphth-1-yl)methyl)-4H-1,2,4-triazol-3-
yl)thio)acetate (1j) and sodium 2-((5-bromo-4-((4-bromonaphth-1-yl)methyl)-4H-1,2,4-triazol-3-
yl)thio)acetate (1m), were identified, which were 78- and 76-fold more active than parent lesinurad
in in vitro URAT1 inhibitory assay, respectively (IC50 values for 1j and 1m were 0.092 μM and
0.094 μM, respectively, against human URAT1 vs 7.18 μM for lesinurad).
Conclusion: Two highly active URAT1 inhibitors were discovered. The SAR exploration also identified
more flexible naphthyltriazolylmethane as a novel molecular skeleton that will be valuable for
the design of URAT1 inhibitors, as indicated by the observation that many of the synthesized naphthyltriazolylmethane-
bearing derivatives (1b-1d, 1g, 1j and 1m) showed significantly improved
UART1 inhibitory activity (sub-micromolar IC50 values) as compared with lesinurad which has the
rigid naphthyltriazole skeleton.