Verinurad (RDEA3170)

Verinurad以濃度依賴性方式抑制人源URAT1的轉(zhuǎn)運(yùn)活性，IC50為25 nM。Verinurad還抑制URAT1相關(guān)同系物OAT4和OAT1，IC50分別為5.9 μM和4.6 μM，親和力較之與URAT低200倍。Verinurad對(duì)人源URAT1比對(duì)大鼠URAT1的親和力高1640倍（human URAT1 IC50=0.025 μM，rat URAT IC50=41 μM）。Verinurad對(duì)人源URAT1具有高效力，URAT1的第35、365和481位殘基有助于verinurad結(jié)合。在人源URAT1在365位引入一個(gè)嵌合點(diǎn)突變（人源365位苯丙氨酸替換成大鼠365位的酪氨酸；h-F365Y），verinurad對(duì)其IC50為4 μM，比對(duì)野生型人源URAT1D低160倍。同時(shí)，如果在輸入U(xiǎn)RAT1引入類似的點(diǎn)突變（即將大鼠365位酪氨酸突變?yōu)槿嗽?65位的苯丙氨酸；r-Y365F），verinurad對(duì)其IC50為2.9 μM，比對(duì)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.

在人體中，Verinurad單藥給藥吸收很快，其暴露量（Cmax和AUC）隨劑量的升高而升高。在饑餓狀態(tài)下，給藥0.5-0.75小時(shí)后達(dá)到Cmax；在進(jìn)食狀態(tài)下，給藥后1.25小時(shí)達(dá)到Cmax。在不同劑量下，t_1/2約為10-15小時(shí)。Verinurad在體內(nèi)耐受性良好。在體循環(huán)中，verinurad具有高清除率（CL/F ranged ~30-50 L/h），廣泛分布在血管外。其腎排泄率低，在尿液中僅2%-3%。大部分verinurad可能在肝臟中通過生物轉(zhuǎn)化形成代謝物^[2]。