URAT1 (urate transporter 1) is a transporter critical for renal reabsorption of urate. Inactivating mutations of URAT1 lead to high FEUA (fractional excretion of uric acid) and hypouricemia (abnormally low sUA (serum uric acid) levels). Verinurad inhibits the transport activity of human URAT1 in a dose-dependent manner, at high potency with an IC50 of 25 nM. And it’s currently under evaluation for the treatment of gout which is caused by elevated serum urate levels. Verinurad inhibits the related URAT1 homologs OAT4 and OAT1 with approximately 200-fold lower affinity compared to URAT1 with IC50 values of 5.9 µM and 4.6 µM, respectively. Therefore, verinurad is highly specific for URAT1. Moreover, human URAT1 has a 1,640-fold higher affinity for verinurad compared to rat URAT1 (IC50 = 41 µM). Consistent with the in vitro inhibition of URAT1, treatment of healthy human volunteers with a single 40 mg dose of verinurad reduced the sUA by up to 60% and increased the FEUA in a dose-dependent manner with a half-maximal effective concentration in plasma of 22 nM[3].
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