Verinurad (RDEA3170)

Verinurad以浓度依赖性方式抑制人源URAT1的转运活性，IC50为25 nM。Verinurad还抑制URAT1相关同系物OAT4和OAT1，IC50分别为5.9 μM和4.6 μM，亲和力较之与URAT低200倍。Verinurad对人源URAT1比对大鼠URAT1的亲和力高1640倍（human URAT1 IC50=0.025 μM，rat URAT IC50=41 μM）。Verinurad对人源URAT1具有高效力，URAT1的第35、365和481位残基有助于verinurad结合。在人源URAT1在365位引入一个嵌合点突变（人源365位苯丙氨酸替换成大鼠365位的酪氨酸；h-F365Y），verinurad对其IC50为4 μM，比对野生型人源URAT1D低160倍。同时，如果在输入URAT1引入类似的点突变（即将大鼠365位酪氨酸突变为人源365位的苯丙氨酸；r-Y365F），verinurad对其IC50为2.9 μM，比对野生型大鼠URAT1高14倍^[1]。

URAT1 and OAT4 activity assays were performed in assay buffer con- sisting of 25 mM MES pH 5.5 (from a 1 M MES solution adjusted to pH 5.5 with sodium hydroxide), 125 mM sodium gluconate, 4.8 mM potassium gluconate, 1.2 mM monobasic potassium phosphate, 1.2 mM magnesium sulfate, 1.3 mM calcium gluconate and 5.6 mM glucose. URAT1 inhibitors were serially diluted into assay buffer and added to the cells for 5 minutes prior to addition of substrate. URAT1-expressing cells were incubated with 100 μM 14C-uric acid for 10 minutes and OAT4-expressing cells were incubated with 20 μM carboxyfluorescein for 5 minutes. Cells were then washed three times in 25 mM MES pH 5.5/125 mM sodium gluconate, and solubilized in Ultima Gold prior to liquid scintillation counting. Each treatment is measured in triplicate.

在人体中，Verinurad单药给药吸收很快，其暴露量（Cmax和AUC）随剂量的升高而升高。在饥饿状态下，给药0.5-0.75小时后达到Cmax；在进食状态下，给药后1.25小时达到Cmax。在不同剂量下，t_1/2约为10-15小时。Verinurad在体内耐受性良好。在体循环中，verinurad具有高清除率（CL/F ranged ~30-50 L/h），广泛分布在血管外。其肾排泄率低，在尿液中仅2%-3%。大部分verinurad可能在肝脏中通过生物转化形成代谢物^[2]。