Background Control of blood uric acid is important for the treatment of gout. The clinical potential of a selective uric acid transporter 1 (URAT1) inhibitor as a drug for hyperuricemia and gout remains unknown because currently available uricosuric drugs block renal uric acid reabsorption by inhibiting not only URAT1 but also other transporters responsible for renal tubular uric acid secretion, such as OAT1 or OAT3. We have identified a highly selective URAT1 inhibitor, UR-1102, which is now under clinical trial for gout. Objectives In this study, we examined the therapeutic potential of selective URAT1 inhibition with UR-1102 by comparing it with benzbromarone, a traditional non-selective URAT1 inhibitor, in vitro and in vivo with cebus monkeys, an animal model that has similar purine metabolism and urinary uric acid excretion to humans. Methods The inhibitory effects of UR-1102 and benzbromarone on URAT1, OAT1, OAT3 and ABCG2 were evaluated in vitro using CHO cells that over-express these transporters. UR-1102 at 3, 10, and 30 mg/kg or benzbromarone at 3, 10, 30, and 100 mg/kg were administered orally once a day to cebus monkeys for 3 consecutive days (n=6, cross-over study). Plasma and urinary excretion of uric acid and creatinine were measured at regular time intervals. Fractional excretion of uric acid (FEUA) was calculated from those values. Results UR-1102 exhibited significantly more potent and highly selective (Ki values for URAT1 were >100 smaller than other transporters) URAT1 inhibition than benzbromarone in vitro, while benzbromarone inhibited URAT1, OAT1, OAT3 and ABCG2 dose-dependently as reported in the literature. The average plasma uric acid concentration for the control group was 3.6 +/- 0.2 mg/dL and FEUA was 8.8% +/- 0.4% on day 3 (0–8 hours after 3rd administration) in the cebus monkeys. Benzbromarone showed dose-dependent and significant reduction of plasma uric acid concentration (3.4, 3.0, 2.8, and 2.7 mg/dL at 3, 10, 30, and 100 mg/kg, respectively) and increase of FEUA (10.3%, 14.5%, 18.5%, and 20.6% at 3, 10, 30, and 100 mg/kg, respectively). UR-1102 also showed the dose-dependent and significant effects on plasma uric acid reduction (2.5, 2.4, and 1.8 mg/dL at 3, 10, and 30 mg/kg, respectively) and increase of FEUA (22.6%, 35.4%, and 42.1% at 3, 10, and 30 mg/kg, respectively). The effects were more apparent for UR-1102 at a lower dose. Moreover, comparing the submaximal dose of UR-1102 at 30 mg/kg with benzbromarone at 100 mg/kg, the effects were significantly higher for UR-1102 than for benzbromarone (plasma uric acid concentration: 1.8 +/- 0.2 mg/dL vs 2.7 +/- 0.2 mg/dL, p<0.01 and FEUA: 42.1% +/- 4.4% vs 20.6% +/- 2.3%, p<0.05). Conclusions Hypouricemic and uricosuric effects were more potent for UR-1102 than for benzbromarone in both dose and maximum efficacy in cebus monkeys. This may be due to the high selectivity of UR-1102 for URAT1. UR-1102 would have greater efficacy as a therapeutic drug for gout/hyperuricemia than benzbromarone. Disclosure of Interest S. O. Ahn Employee of: C&C Research Laboratories, N. Horiba Employee of: Chugai Pharmaceutical Co., Ltd., S. Ohtomo Employee of: Chugai Pharmaceutical Co., Ltd., K. J. Lee Employee of: C&C Research Laboratories, K. H. Kim Employee of: C&C Research Laboratories, B. H. Kim Employee of: C&C Research Laboratories, J. Kiyokawa Employee of: Chugai Pharmaceutical Co., Ltd., M. Yamane Employee of: Chugai Pharmaceutical Co., Ltd., H. Ikegami Employee of: Chugai Pharmaceutical Co., Ltd., T. Nakagawa Employee of: Chugai Pharmaceutical Co., Ltd., H.-H. Hwang Employee of: JW Pharmaceutical corp., J.-H. PARK Employee of: JW Pharmaceutical corp., J. Y. Cha Employee of: JW Pharmaceutical corp., J. Tanaka Employee of: Shin Nippon Biomedical Laboratories, Ltd., T. Kake Employee of: Chugai Pharmaceutical Co., Ltd.

中文翻译：

---

SAT0356 新型促尿酸排泄剂 UR-1102 治疗高尿酸血症和痛风的疗效

背景 血尿酸的控制对于痛风的治疗很重要。选择性尿酸转运蛋白 1 (URAT1) 抑制剂作为治疗高尿酸血症和痛风的药物的临床潜力仍然未知，因为目前可用的尿酸排泄药物不仅通过抑制 URAT1 还通过抑制其他负责肾小管尿酸分泌的转运蛋白来阻断肾尿酸重吸收，例如 OAT1 或 OAT3。我们已经确定了一种高度选择性的 URAT1 抑制剂 UR-1102，目前正在对痛风进行临床试验。目的 在本研究中，我们通过将 UR-1102 与苯溴马隆（一种传统的非选择性 URAT1 抑制剂）在 cebus 猴（一种具有相似嘌呤代谢和尿尿酸对人体的排泄。方法 使用过度表达这些转运蛋白的 CHO 细胞，体外评估 UR-1102 和苯溴马隆对 URAT1、OAT1、OAT3 和 ABCG2 的抑制作用。将 3、10 和 30 mg/kg 的 UR-1102 或 3、10、30 和 100 mg/kg 的苯溴马隆每天一次口服给药至 cebus 猴，连续 3 天（n=6，交叉研究） . 定期测量血浆和尿中尿酸和肌酐的排泄量。从这些值计算尿酸排泄分数 (FEUA)。结果 UR-1102 在体外表现出比苯溴马隆更有效和高度选择性（URAT1 的 Ki 值比其他转运蛋白小 >100）URAT1 抑制作用，而苯溴马隆抑制 URAT1、OAT1、OAT3 和 ABCG2 呈剂量依赖性，如文献报道。在第 3 天（第 3 次给药后 0-8 小时），对照组的平均血浆尿酸浓度为 3.6 +/- 0.2 mg/dL，FEUA 为 8.8% +/- 0.4%。苯溴马隆显示出血浆尿酸浓度的剂量依赖性显着降低（分别为 3、10、30 和 100 mg/kg 时的 3.4、3.0、2.8 和 2.7 mg/dL）和 FEUA 的增加（10.3%、14.5%） 、18.5% 和 20.6%，分别为 3、10、30 和 100 mg/kg）。UR-1102 还显示出对血浆尿酸降低（分别为 3、10 和 30 mg/kg 时的 2.5、2.4 和 1.8 mg/dL）和 FEUA 增加（22.6%、35.4%）的剂量依赖性和显着影响和 42.1%，分别为 3、10 和 30 mg/kg）。UR-1102 在较低剂量下的效果更明显。此外，将 30 mg/kg 的 UR-1102 的次最大剂量与 100 mg/kg 的苯溴马隆进行比较，UR-1102 的效果显着高于苯溴马隆（血浆尿酸浓度：1.8 +/- 0.2 mg/dL vs 2.7 +/- 0.2 mg/dL，p<0.01 和 FEUA：42.1% +/- 4.4% vs 20.6% +/- 2.3%，p<0.05)。结论 UR-1102 的降尿酸和促尿酸排泄作用在 cebus 猴的剂量和最大功效方面比苯溴马隆更有效。这可能是由于 UR-1102 对 URAT1 的高选择性。UR-1102 作为痛风/高尿酸血症的治疗药物比苯溴马隆更有效。利益披露 SO Ahn 员工：C&C Research Laboratories, N. Horiba 员工：Chugai Pharmaceutical Co., Ltd., S. Ohtomo 员工：Chugai Pharmaceutical Co., Ltd., KJ Lee 员工：C&C Research Laboratories, KH Kim 员工：C&C Research Laboratories, BH Kim 员工：C& C Research Laboratories, J. Kiyokawa 员工：Chugai Pharmaceutical Co., Ltd., M. Yamane 员工：Chugai Pharmaceutical Co., Ltd.，H. Ikegami 员工：Chugai Pharmaceutical Co., Ltd.，T. Nakagawa 员工作者：中外制药有限公司，H.-H. Hwang 员工：JW Pharmaceutical corp., J.-H. PARK 员工：JW Pharmaceutical corp.、JY Cha 员工：JW Pharmaceutical corp.、J. Tanaka 员工：Shin Nippon Biomedical Laboratories, Ltd.、T. Kake 员工：Chugai Pharmaceutical Co., Ltd.