Identification

Name
Lesinurad
Accession Number
DB11560
Type
Small Molecule
Groups
Approved, Investigational
Description

Lesinurad is an oral uric acid transporter 1 (URAT1) inhibitor indicated for the treatment of hyperuricemia associated with gout. It reduces serum uric acid concentration through the inhibition of URAT1, an enzyme responsible for reuptake of uric acid from the renal tubule, and OAT4, another uric acid transporter associated with diuretic-induced hyperuricemia.

Marketed as the product Zurampic, it is indicated for use in combination with a xanthine oxidase inhibitor for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone. In August 2017, a combination oral therapy consisting of lesinurad and Allopurinol was FDA-approved under the brand name Duzallo indicated for the treatment of gout-related hyperuricemia in patients with uncontrolled gout.

Structure
Thumb
Synonyms
  • {[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid
External IDs
RDEA 594 / RDEA-594 / RDEA594
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ZurampicTablet, film coated200 mgOralGrunenthal Gmb H2016-02-18Not applicableEu
ZurampicTablet, film coated200 mgOralGrunenthal Gmb H2016-02-18Not applicableEu
ZurampicTablet, film coated200 mg/1OralIronwood Pharmaceuticals, Inc.2017-10-03Not applicableUs
ZurampicTablet, film coated200 mgOralGrunenthal Gmb H2016-02-18Not applicableEu
ZurampicTablet, film coated200 mgOralGrunenthal Gmb H2016-02-18Not applicableEu
ZurampicTablet, film coated200 mgOralGrunenthal Gmb H2016-02-18Not applicableEu
ZurampicTablet, film coated200 mg/1OralAstraZeneca Pharmaceuticals LP2016-08-11Not applicableUs
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
DuzalloLesinurad (200 mg/1) + Allopurinol (200 mg/1)Tablet, film coatedOralIronwood Pharmaceuticals, Inc.2017-10-03Not applicableUs
DuzalloLesinurad (200 mg/1) + Allopurinol (300 mg/1)Tablet, film coatedOralIronwood Pharmaceuticals, Inc.2017-10-03Not applicableUs
Categories
UNII
09ERP08I3W
CAS number
878672-00-5
Weight
Average: 404.28
Monoisotopic: 402.999011
Chemical Formula
C17H14BrN3O2S
InChI Key
FGQFOYHRJSUHMR-UHFFFAOYSA-N
InChI
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)
IUPAC Name
2-{[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid
SMILES
OC(=O)CSC1=NN=C(Br)N1C1=CC=C(C2CC2)C2=C1C=CC=C2

Pharmacology

Indication

For use, in combination with a xanthine oxidase inhibitor, for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone.

Associated Conditions
Pharmacodynamics

Dose-dependent reductions in serum uric acid levels and increases in urinary uric acid excretion have been observed following single and multiple oral doses of lesinurad.

Mechanism of action

Lesinurad inhibits the activity of uric acid transporter 1 (URAT1) and organic anion transporter 4 (OAT4). URAT1 is a major transporter enzyme responsible for reuptake of uric acid from the renal tubules; inhibition of URAT1 function thereby increases excretion of uric acid.

TargetActionsOrganism
ASolute carrier family 22 member 12
inhibitor
Human
ASolute carrier family 22 member 11
inhibitor
Human
Absorption

Oral lesinurad is rapidly absorbed, reaching maximum plasma concentrations (Cmax) within 1–4 h following the administration a single 200 mg dose (in either the fed or fasted state).

Volume of distribution

The mean steady state volume of distribution of lesinurad was approximately 20 L following intravenous dosing.

Protein binding

Lesinurad is extensively bound to proteins in plasma (greater than 98%), mainly to albumin.

Metabolism

Lesinurad undergoes oxidative metabolism mainly via the polymorphic cytochrome P450 CYP2C9 enzyme.

Route of elimination

Within 7 days following single dosing of radiolabeled lesinurad, 63% of administered radioactive dose was recovered in urine and 32% of administered radioactive dose was recovered in feces. Most of the radioactivity recovered in urine (> 60% of dose) occurred in the first 24 hours. Unchanged lesinurad in urine accounted for approximately 30% of the dose.

Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Cytochrome P450 2C9CYP2C9*2Not Available430C>TEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C9CYP2C9*3Not Available1075A>CEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C9CYP2C9*4Not Available1076T>CEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C9CYP2C9*5Not Available1080C>GEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C9CYP2C9*8Not Available449G>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C9CYP2C9*11Not Available1003C>TEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C9CYP2C9*12Not Available1465C>TEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C9CYP2C9*13Not Available269T>CEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C9CYP2C9*14Not Available374G>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C9CYP2C9*16Not Available895A>GEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C9CYP2C9*18Not Available1075A>C / 1190A>C  … show all Effect InferredPoor drug metabolizer.Details
Cytochrome P450 2C9CYP2C9*26Not Available389C>GEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C9CYP2C9*28Not Available641A>TEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C9CYP2C9*30Not Available1429G>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C9CYP2C9*33Not Available395G>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C9CYP2C9*6Not Available818delAEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C9CYP2C9*15Not Available485C>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C9CYP2C9*25Not Available353_362delAGAAATGGAAEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C9CYP2C9*35Not Available374G>T / 430C>TEffect InferredPoor drug metabolizer.Details

Interactions

Drug Interactions
DrugInteraction
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Lesinurad.
AbacavirAbacavir may decrease the excretion rate of Lesinurad which could result in a higher serum level.
AbirateroneThe metabolism of Lesinurad can be decreased when combined with Abiraterone.
AcarboseAcarbose may decrease the excretion rate of Lesinurad which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Lesinurad which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Lesinurad which could result in a higher serum level.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Lesinurad.
AcetaminophenAcetaminophen may decrease the excretion rate of Lesinurad which could result in a higher serum level.
AcetohexamideThe metabolism of Lesinurad can be decreased when combined with Acetohexamide.
Acetyl sulfisoxazoleThe metabolism of Lesinurad can be decreased when combined with Acetyl sulfisoxazole.
Food Interactions
Not Available

References

General References
  1. Hoy SM: Lesinurad: First Global Approval. Drugs. 2016 Mar;76(4):509-16. doi: 10.1007/s40265-016-0550-y. [PubMed:26861027]
External Links
KEGG Drug
D09921
PubChem Compound
53465279
PubChem Substance
347827983
ChemSpider
28527877
ChEBI
90929
ChEMBL
CHEMBL2105720
PharmGKB
PA166160006
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Lesinurad
ATC Codes
M04AB05 — Lesinurad
FDA label
Download (642 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceAcute Gouty Arthritis1
1CompletedBasic ScienceHealthy Volunteers6
1CompletedTreatmentAcute Gouty Arthritis1
1CompletedTreatmentHealthy Volunteers2
1Enrolling by InvitationTreatmentAcute Gouty Arthritis1
2CompletedTreatmentAcute Gouty Arthritis1
2CompletedTreatmentHyperuricemia1
3CompletedTreatmentAcute Gouty Arthritis6
3CompletedTreatmentTophaceous Gout1
4RecruitingTreatmentAcute Gouty Arthritis / Chronic Kidney Disease (CKD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral
Tablet, film coatedOral200 mg
Tablet, film coatedOral200 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8283369No2012-10-092028-11-26Us
US8084483No2011-12-272029-08-17Us
US8357713No2013-01-222028-11-26Us
US8546437No2013-10-012029-04-29Us
US9216179No2015-12-222030-08-02Us
US8003681No2011-08-232025-08-25Us
US8546436No2013-10-012032-02-29Us
US9956205No2018-05-012031-12-28Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00779 mg/mLALOGPS
logP3.42ALOGPS
logP4.09ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)3.13ChemAxon
pKa (Strongest Basic)-0.05ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area68.01 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity109.15 m3·mol-1ChemAxon
Polarizability36.59 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenyl-1,2,4-triazoles. These are organic compounds containing a 1,2,4-triazole substituted by a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azoles
Sub Class
Triazoles
Direct Parent
Phenyl-1,2,4-triazoles
Alternative Parents
Naphthalenes / Alkylarylthioethers / Aryl bromides / Heteroaromatic compounds / Sulfenyl compounds / Monocarboxylic acids and derivatives / Carboxylic acids / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds
show 4 more
Substituents
Phenyl-1,2,4-triazole / Naphthalene / Aryl thioether / Alkylarylthioether / Aryl bromide / Aryl halide / Benzenoid / Heteroaromatic compound / Carboxylic acid derivative / Carboxylic acid
show 16 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Urate transmembrane transporter activity
Specific Function
Required for efficient urate re-absorption in the kidney. Regulates blood urate levels. Mediates saturable urate uptake by facilitating the exchange of urate against organic anions.
Gene Name
SLC22A12
Uniprot ID
Q96S37
Uniprot Name
Solute carrier family 22 member 12
Molecular Weight
59629.57 Da
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates saturable uptake of estrone sulfate, dehydroepiandrosterone sulfate and related compounds.
Gene Name
SLC22A11
Uniprot ID
Q9NSA0
Uniprot Name
Solute carrier family 22 member 11
Molecular Weight
59970.945 Da

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Lesinurad FDA Label [File]

Drug created on March 09, 2016 20:25 / Updated on November 02, 2018 07:12