Background/Purpose: In most patients with gout, renal underexcretion of uric acid is the main mechanism for hyperuricemia. However, for the risk of uric acid kidney stone, uricosuric drugs are second-line treatment for hyperuricemia. It is also known that low urinary pH significantly increases the risk of uric acid crystallization and is strongly related with insulin resistance.  Patients with gout frequently have metabolic syndrome, closely associated with insulin resistance. In this study, we describe a novel potent urate transporter 1 (URAT1) inhibitor, NC-2700, with pH-raising effect on low urinary pH.

Methods: HEK 293 cells stably expressing URAT1 were treated with NC-2700, verinurad or lesinurad, and the inhibitory activity was determined by measuring the uptake of [¹⁴C]uric acid into the cells. To determine the selectivity of NC-2700 to URAT1, the effects on other transporters, including OAT1, OAT3 and ABCG2 were tested. The uricosuric effect and pH-raising effect of NC-2700 on low urinary pH were evaluated following single and/or multiple (once a day) doses in tufted capuchin monkeys and Zucker diabetic fatty rats (ZDF rats, type 2 diabetic model), respectively.

Results: NC-2700 inhibited URAT1 concentration-dependently with Ki value of 31.4 nmol/L. Inhibitory activity of NC-2700 against URAT1 was about 3-fold and roughly 1000-fold stronger than those of verinurad and lesinurad. In addition, NC-2700 showed high selectivity to URAT1 over other transporters. In in vivo studies, NC-2700 dose-dependently increased the fractional excretion of urinary uric acid in tufted capuchin monkeys and the effect of NC-2700 was great compared with verinurad. Moreover, unlike verinurad, NC-2700 raised urine pH levels lowered in ZDF rats to normal levels.

Conclusion: NC-2700 is a novel potent and highly selective URAT1 inhibitor, and has not just a great uricosuric effect compared with verinurad in monkeys, but also pH-raising effect on low urinary pH in ZDF rats. NC-2700 is a promising candidate for the treatment of patients with gout and hyperuricemia, which could decrease the risk of renal calculus and nephrotoxicity with urate crystals in the urine, the most common issue with uricosuric therapy.