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Details

Stereochemistry RACEMIC
Molecular Formula C17H14BrN3O2S
Molecular Weight 404.281
Optical Activity ( + / - )
Additional Stereochemistry Yes
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0
Stereo Comments AXIAL, RACEMIC

SHOW SMILES / InChI
Structure of LESINURAD

SMILES

OC(=O)CSC1=NN=C(Br)N1C2=C3C=CC=CC3=C(C=C2)C4CC4

InChI

InChIKey=FGQFOYHRJSUHMR-UHFFFAOYSA-N
InChI=1S/C17H14BrN3O2S/c18-16-19-20-17(24-9-15(22)23)21(16)14-8-7-11(10-5-6-10)12-3-1-2-4-13(12)14/h1-4,7-8,10H,5-6,9H2,(H,22,23)

HIDE SMILES / InChI

Description

Lesinurad (brand name Zurampic) is a urate transporter inhibitor for treating hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone. In gout patients, Lesinurad lowered serum uric acid levels and increased renal clearance and fractional excretion of uric acid. Following single and multiple oral doses of Lesinurad to gout patients, dose-dependent decreases in serum uric acid levels and increases in urinary uric acid excretion were observed. Lesinurad reduces serum uric acid levels by inhibiting the function of transporter proteins involved in uric acid reabsorption in the kidney. Lesinurad inhibited the function of two apical transporters responsible for uric acid reabsorption, uric acid transporter 1 (URAT1) and organic anion transporter 4 (OAT4), with IC50 values of 7.3 and 3.7 µM, respectively. URAT1 is responsible for the majority of the reabsorption of filtered uric acid from the renal tubular lumen. OAT4 is a uric acid transporter associated with diuretic-induced hyperuricemia. Lesinurad does not interact with the uric acid reabsorption transporter SLC2A9 (Glut9), located on the basolateral membrane of the proximal tubule cell. Based on in vitro studies, lesinurad is an inhibitor of OATP1B1, OCT1, OAT1, and OAT3; however, lesinurad is not an in vivo inhibitor of these transporters. In vivo drug interaction studies indicate that lesinurad does not decrease the renal clearance of furosemide (substrate of OAT1/3), or affect the exposure of atorvastatin (substrate of OATP1B1) or metformin (substrate of OCT1). Based on in vitro studies, lesinurad has no relevant effect on P-glycoprotein.

CNS Activity

Originator

Approval Year

Targets

Primary TargetPharmacologyConditionPotency
7.3 µM [IC50]
3.7 µM [IC50]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Secondary
ZURAMPIC

Cmax

ValueDoseCo-administeredAnalytePopulation
0.303 μg/mL
5 mg single, oral
LESINURAD plasma
Homo sapiens
3.21 μg/mL
100 mg single, oral
LESINURAD plasma
Homo sapiens
22 μg/mL
600 mg single, oral
LESINURAD plasma
Homo sapiens
4.02 μg/mL
100 mg 1 times / day multiple, oral
LESINURAD plasma
Homo sapiens
4.74 μg/mL
100 mg single, oral
LESINURAD plasma
Homo sapiens
7.68 μg/mL
100 mg single, oral
LESINURAD plasma
Homo sapiens
10.8 μg/mL
200 mg single, oral
LESINURAD plasma
Homo sapiens
1.54 μg/mL
25 mg single, oral
LESINURAD plasma
Homo sapiens
6.51 μg/mL
200 mg 1 times / day multiple, oral
LESINURAD plasma
Homo sapiens
11.8 μg/mL
200 mg single, oral
LESINURAD plasma
Homo sapiens
11.7 μg/mL
200 mg 1 times / day multiple, oral
LESINURAD plasma
Homo sapiens
17.7 μg/mL
400 mg single, oral
LESINURAD plasma
Homo sapiens
23.1 μg/mL
400 mg single, oral
LESINURAD plasma
Homo sapiens
21.9 μg/mL
400 mg 1 times / day multiple, oral
LESINURAD plasma
Homo sapiens
5.54 μg/mL
200 mg single, oral
LESINURAD plasma
Homo sapiens

AUC

ValueDoseCo-administeredAnalytePopulation
0.787 μg × h/mL
5 mg single, oral
LESINURAD plasma
Homo sapiens
10.9 μg × h/mL
100 mg single, oral
LESINURAD plasma
Homo sapiens
106 μg × h/mL
600 mg single, oral
LESINURAD plasma
Homo sapiens
12.1 μg × h/mL
100 mg 1 times / day multiple, oral
LESINURAD plasma
Homo sapiens
14.2 μg × h/mL
100 mg single, oral
LESINURAD plasma
Homo sapiens
17.5 μg × h/mL
100 mg single, oral
LESINURAD plasma
Homo sapiens
28.7 μg × h/mL
200 mg single, oral
LESINURAD plasma
Homo sapiens
3.12 μg × h/mL
25 mg single, oral
LESINURAD plasma
Homo sapiens
30.3 μg × h/mL
200 mg 1 times / day multiple, oral
LESINURAD plasma
Homo sapiens
31.9 μg × h/mL
200 mg single, oral
LESINURAD plasma
Homo sapiens
33.1 μg × h/mL
200 mg 1 times / day multiple, oral
LESINURAD plasma
Homo sapiens
56.4 μg × h/mL
400 mg single, oral
LESINURAD plasma
Homo sapiens
70.5 μg × h/mL
400 mg single, oral
LESINURAD plasma
Homo sapiens
89.8 μg × h/mL
400 mg 1 times / day multiple, oral
LESINURAD plasma
Homo sapiens
29.8 μg × h/mL
200 mg single, oral
LESINURAD plasma
Homo sapiens

T1/2

ValueDoseCo-administeredAnalytePopulation
2.73 h
5 mg single, oral
LESINURAD plasma
Homo sapiens
34.6 h
100 mg single, oral
LESINURAD plasma
Homo sapiens
8.04 h
600 mg single, oral
LESINURAD plasma
Homo sapiens
10.6 h
100 mg 1 times / day multiple, oral
LESINURAD plasma
Homo sapiens
4.23 h
100 mg single, oral
LESINURAD plasma
Homo sapiens
12.7 h
100 mg single, oral
LESINURAD plasma
Homo sapiens
4.72 h
200 mg single, oral
LESINURAD plasma
Homo sapiens
3.99 h
25 mg single, oral
LESINURAD plasma
Homo sapiens
8.2 h
200 mg 1 times / day multiple, oral
LESINURAD plasma
Homo sapiens
5.97 h
200 mg single, oral
LESINURAD plasma
Homo sapiens
8.91 h
200 mg 1 times / day multiple, oral
LESINURAD plasma
Homo sapiens
5.19 h
400 mg single, oral
LESINURAD plasma
Homo sapiens
8.91 h
400 mg single, oral
LESINURAD plasma
Homo sapiens
7.48 h
400 mg 1 times / day multiple, oral
LESINURAD plasma
Homo sapiens
3.77 h
200 mg single, oral
LESINURAD plasma
Homo sapiens

Doses

Drug as perpetrator​

Drug as victim

Tox targets

Sample Use Guides

In Vivo Use Guide
ZURAMPIC (Lesinurad ) is recommended at 200 mg once daily in combination with a xanthine oxidase inhibitor, including allopurinol or febuxostat. The maximum daily dose of ZURAMPIC is 200 mg.
Route of Administration: Oral
In Vitro Use Guide
OAT1 was expressed in Flp-In 293 cells. [14C]RDEA594 was incubated with cells for 5 minutes at 37C. The reaction was stopped with ice-cold transport medium and cells were lysed with 0.2 ml of 1 N NAOH and radioactivity was measured using liquid scintillation counting. There was saturable uptake of [14C]RDEA594 into oocytes expressing OAT1. The Km was 0.85 μM and Vmax was 13.0 pmol/min/mg protein