Topiroxostat

Identification

Generic Name

Topiroxostat

DrugBank Accession Number

DB01685

Background

Topiroxostat is a selective xanthine oxidase inhibitor developed for treatment and management of hyperuricemia and gout. Xanthine oxidase, or xanthine oxidoreductase (XOR), regulates purine metabolism, and inhibition of the enzyme results in efficacious reduction of serum urate levels. Xanthine oxidase inhibitors are classified into two groups; purine analogs such as Allopurinol and Oxypurinol, and non-purine agents which includes topiroxostat. While Allopurinol is considered a first-line therapy in treating hyperuricemic conditions, it is often associated with side effects and ineffective in reducing uric acid levels under recommended dosing regimens. Renal complications are major comorbidities that limit the Allopurinol therapy as dose reductions are recommended. Topiroxostat and its metabolites are shown to be unaffected by renal complications, thus may be effective in patients with chronic kidney diseases ². Approved for therapeutic use in Japan since 2013, topiroxostat is marketed under the name Topiloric and Uriadec and is orally administered twice daily.

Type

Small Molecule

Groups

Experimental

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Topiroxostat (DB01685)

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Weight

Average: 248.2428
Monoisotopic: 248.081044286

Chemical Formula

C₁₃H₈N₆

Synonyms

• 4-(5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl)pyridine-2-carbonitrile
• Topiroxostat

External IDs

• FYX-051

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Pharmacology

Indication

Indicated for the treatment of gout and hyperurcemia in Japan.

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Contraindications & Blackbox Warnings

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Pharmacodynamics

Topiroxostat reduces the synthesis of uric acid by competitively inhibiting xanthine oxidase in a selective and time-dependent manner ¹. It serves to reduce the concentration of insoluble urates and uric acid in tissues, plasma and urine. Topiroxostat is not reported to cause QT prolongation ⁴.

Mechanism of action

Uric acid synthesis depends on the action of xanthine oxidase activity in the conversion of hypoxanthine to xanthine, followed by the conversion of xanthine to uric acid. Xanthine oxidase consists of a molybdenum ion as cofactor in the active center that has different redox states upon substrate binding ¹⁰. When a substrate such as hypoxanthine or xanthine binds, xanthine oxidase hydroxylates it and molybdenum ion is reduced from hexavalent, Mo(VI), to tetravalent form, Mo(IV). Molybdenum ion is reoxidized into hexavalent state once the hydroxylated substrate, xanthine or uric acid, dissociates from the active site. Topiroxostat is shown to interact with multiple amino acid residues of the solvent channel and additionally forms a reaction intermediate by covalent binding with molybdenum (IV) ion via an oxygen atom ^2,10,5,6. It also forms hydrogen bonds with molybdenum (VI) ion, suggesting that it has multiple inhibition modes to xanthine oxidase ¹⁰. Enhanced binding interactions to xanthine oxidase achieves delayed dissociation of topiroxostat from the enzyme. 2-hydroxy-topiroxostat, the metabolite formed by primary hydroxylation of topiroxostat by xanthine oxidase, also causes time and concentration-dependent inhibition of the enzyme ¹. Topiroxostat is shown to inhibit ATP-binding cassette transporter G2 (ABCG2) in vitro, which is a membrane protein responsible for recovering uric acid in the kidneys and secreting uric acid from the intestines ^3,9.

Target	Actions	Organism
UXanthine dehydrogenase/oxidase	Not Available	Humans

Absorption

The time to reach peak plasma concentration of 229.9 ng/mL was 0.67 hour following a single oral dose of 20mg topiroxostat ¹⁰. The oral bioavailability in male rats was 69.6% after oral administration of a single dose of 1mg/kg ¹⁰.

Volume of distribution

The distribution of 14C-topiroxostat (20, 200, and 2000 ng/mL) in human blood cells was 6.7% to 12.8% ¹⁰.

Protein binding

The mean protein binding of radiolabeled (14C)-topiroxostat in human plasma is >97.5% at 20ng/mL, 98.8% at 200ng/mL, and 98.4% at 2000ng/mL. Binding to serum albumin is most predominant with 92.3-93.2%, and mean protein binding to α1-acid protein and γ-globulin is 12.3% to 16.8% and 34.7% to 40.4%, respectively ¹⁰.

Metabolism

Topiroxostat is mainly inactivated by hepatic metabolism. 2-hydroxy topiroxostat is formed from primary hydroxylation of the drug by xanthine oxidase and still retains an inhibitory activity on the enzyme ¹. Topiroxostat N-oxide is another major metabolite that can be detected in plasma and urine. It is determined that the N-oxide and hydroxide metabolites are pyridine N-oxide and pyridine 2 (or 6)-hydroxide, respectively ⁷. Topiroxostat is mainly inactivated by hepatic metabolism where it undergoes glucuronidation. The metabolism of topiroxostat to N1-and N2-glucuronide conjugates is mainly mediated by UGT1A1, 1A7, and 1A9, with UGT1A9 being the most predominant ¹⁰.

Hover over products below to view reaction partners

• Topiroxostat
  • 2-hydroxy-topiroxostat
  • Topiroxostat N-oxide

Route of elimination

Urinary excretion and fecal excretion of radiolabeled topiroxostat are 30.4% and 40.9% of total dose of 1mg/kg administered to rats, respectively. Within 24 h after a single oral administration of 120mg of topiroxostat, the main metabolites of topiroxostat, N-oxide, N1-gluculonide, and N2-gluculonide, are excreted into urine about 4.8, 43.3, and 16.1 % of the dose, respectively. Unchanged topiroxostat and the hydroxide metabolite was 0.1% or less ⁷.

Half-life

The mean half life of topiroxostat after a single oral dose of 20mg topiroxostat is 5 hours under fasting condition. The complex of molybdenum (IV)- topiroxostat has an approximate half life of 20.4 hours ¹⁰.

Clearance

The apparent total body clearance rate is 89.5 L/h and the renal clearance rate is 17.4 mL/h following a single oral dose of 20mg topiroxostat ¹⁰.

Adverse Effects

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Toxicity

Topiroxostat is not reported to be carcinogenic, genotoxic, or teratogenic ¹⁰. Some reported adverse events of topiroxostat therapy include nasopharyngitis, pain in extremity, elevated alanine aminotransferase (ALT), decreased white blood cell count, eczema and gout arthritis. The no-observed-adverse-effect-level (NOAEL) was determined to be ≥300 mg/kg/day in a study of once-daily, 52-week oral administration of 0/10/30/100 mg/kg/day topiroxostat in monkeys ¹⁰.

Pathways

Not Available

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Interactions

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This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abacavir	Abacavir may decrease the excretion rate of Topiroxostat which could result in a higher serum level.
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Topiroxostat.
Abrocitinib	The metabolism of Abrocitinib can be decreased when combined with Topiroxostat.
Acalabrutinib	The serum concentration of Acalabrutinib can be increased when it is combined with Topiroxostat.
Acamprosate	The excretion of Acamprosate can be decreased when combined with Topiroxostat.

Food Interactions

Not Available

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International/Other Brands

Topiloric (Fujiyakuhin Co.) / Uriadec (Sanwa Kagaku Kenkyusho Co.)

Categories

Drug Categories

• BCRP/ABCG2 Inhibitors
• Cytochrome P-450 CYP2C19 Inhibitors
• Cytochrome P-450 CYP2C19 inhibitors (strength unknown)
• Cytochrome P-450 CYP2C8 Inhibitors
• Cytochrome P-450 CYP2C8 Inhibitors (moderate)
• Cytochrome P-450 CYP2C9 Inhibitors
• Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
• Cytochrome P-450 Enzyme Inhibitors
• Drugs that are Mainly Renally Excreted
• Enzyme Inhibitors
• OAT1/SLC22A6 inhibitors
• OAT3/SLC22A8 Inhibitors
• UGT1A9 Substrates

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as pyridyl-1,2,4-triazoles. These are organic compounds containing a pyridine ring attached to a 1,2,4-triazole ring.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Pyridines and derivatives

Sub Class

Pyridyltriazoles

Direct Parent

Pyridyl-1,2,4-triazoles

Alternative Parents

Triazoles / Heteroaromatic compounds / Nitriles / Azacyclic compounds / Organopnictogen compounds / Hydrocarbon derivatives

Substituents

1,2,4-triazole / Aromatic heteromonocyclic compound / Azacycle / Azole / Carbonitrile / Heteroaromatic compound / Hydrocarbon derivative / Nitrile / Organic nitrogen compound / Organonitrogen compound

Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

Not Available

Affected organisms

Not Available

Chemical Identifiers

UNII

0J877412JV

CAS number

577778-58-6

InChI Key

UBVZQGOVTLIHLH-UHFFFAOYSA-N

InChI

InChI=1S/C13H8N6/c14-8-11-7-10(3-6-16-11)13-17-12(18-19-13)9-1-4-15-5-2-9/h1-7H,(H,17,18,19)

IUPAC Name

4-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile

SMILES

N#CC1=NC=CC(=C1)C1=NNC(=N1)C1=CC=NC=C1

References

General References

1. Matsumoto K, Okamoto K, Ashizawa N, Nishino T: FYX-051: a novel and potent hybrid-type inhibitor of xanthine oxidoreductase. J Pharmacol Exp Ther. 2011 Jan;336(1):95-103. doi: 10.1124/jpet.110.174540. Epub 2010 Oct 15. [Article]
2. Hosoya T, Ohno I, Nomura S, Hisatome I, Uchida S, Fujimori S, Yamamoto T, Hara S: Effects of topiroxostat on the serum urate levels and urinary albumin excretion in hyperuricemic stage 3 chronic kidney disease patients with or without gout. Clin Exp Nephrol. 2014 Dec;18(6):876-84. doi: 10.1007/s10157-014-0935-8. Epub 2014 Jan 22. [Article]
3. Nishino T, Okamoto K: Mechanistic insights into xanthine oxidoreductase from development studies of candidate drugs to treat hyperuricemia and gout. J Biol Inorg Chem. 2015 Mar;20(2):195-207. doi: 10.1007/s00775-014-1210-x. Epub 2014 Dec 12. [Article]
4. Sugiyama A, Hashimoto H, Nakamura Y, Fujita T, Kumagai Y: QT/QTc study conducted in Japanese adult healthy subjects: a novel xanthine oxidase inhibitor topiroxostat was not associated with QT prolongation. J Clin Pharmacol. 2014 Apr;54(4):446-52. doi: 10.1002/jcph.226. Epub 2013 Nov 22. [Article]
5. Okamoto K, Eger BT, Nishino T, Kondo S, Pai EF, Nishino T: An extremely potent inhibitor of xanthine oxidoreductase. Crystal structure of the enzyme-inhibitor complex and mechanism of inhibition. J Biol Chem. 2003 Jan 17;278(3):1848-55. Epub 2002 Nov 5. [Article]
6. Okamoto K, Matsumoto K, Hille R, Eger BT, Pai EF, Nishino T: The crystal structure of xanthine oxidoreductase during catalysis: implications for reaction mechanism and enzyme inhibition. Proc Natl Acad Sci U S A. 2004 May 25;101(21):7931-6. Epub 2004 May 17. [Article]
7. Nakazawa T, Miyata K, Omura K, Iwanaga T, Nagata O: Metabolic profile of FYX-051 (4-(5-pyridin-4-yl-1h-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile) in the rat, dog, monkey, and human: identification of N-glucuronides and N-glucosides. Drug Metab Dispos. 2006 Nov;34(11):1880-6. Epub 2006 Aug 16. [Article]
8. Omura K, Nakazawa T, Sato T, Iwanaga T, Nagata O: Characterization of N-glucuronidation of 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl) pyridine-2-carbonitrile (FYX-051): a new xanthine oxidoreductase inhibitor. Drug Metab Dispos. 2007 Dec;35(12):2143-8. Epub 2007 Aug 30. [Article]
9. Miyata H, Takada T, Toyoda Y, Matsuo H, Ichida K, Suzuki H: Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations. Front Pharmacol. 2016 Dec 27;7:518. doi: 10.3389/fphar.2016.00518. eCollection 2016. [Article]
10. Pharmaceuticals and Medical Devices Agency (PMDA): Topiroxostat review [Link]

External Links

PubChem Compound

5288320

PubChem Substance

46508374

ChemSpider

4450517

BindingDB

50311275

ChEMBL

CHEMBL1078685

ZINC

ZINC000013536586

PDBe Ligand

FYX

Wikipedia

Topiroxostat

PDB Entries

1v97

MSDS

Download (23.9 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
2	Completed	Basic Science	Hyperuricemia	1
2	Completed	Treatment	Diabetic Nephropathy	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Not Available

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0779 mg/mL	ALOGPS
logP	1.47	ALOGPS
logP	1.82	Chemaxon
logS	-3.5	ALOGPS
pKa (Strongest Acidic)	8.75	Chemaxon
pKa (Strongest Basic)	3.91	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	5	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	91.14 Å2	Chemaxon
Rotatable Bond Count	2	Chemaxon
Refractivity	90.47 m3·mol-1	Chemaxon
Polarizability	25.39 Å3	Chemaxon
Number of Rings	3	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	1.0
Blood Brain Barrier	+	0.9553
Caco-2 permeable	+	0.5089
P-glycoprotein substrate	Non-substrate	0.8142
P-glycoprotein inhibitor I	Non-inhibitor	0.914
P-glycoprotein inhibitor II	Non-inhibitor	0.9566
Renal organic cation transporter	Non-inhibitor	0.743
CYP450 2C9 substrate	Non-substrate	0.8646
CYP450 2D6 substrate	Non-substrate	0.8876
CYP450 3A4 substrate	Non-substrate	0.7258
CYP450 1A2 substrate	Inhibitor	0.84
CYP450 2C9 inhibitor	Non-inhibitor	0.8298
CYP450 2D6 inhibitor	Non-inhibitor	0.9604
CYP450 2C19 inhibitor	Non-inhibitor	0.7387
CYP450 3A4 inhibitor	Inhibitor	0.5479
CYP450 inhibitory promiscuity	High CYP Inhibitory Promiscuity	0.6341
Ames test	AMES toxic	0.6839
Carcinogenicity	Non-carcinogens	0.8822
Biodegradation	Not ready biodegradable	1.0
Rat acute toxicity	1.8791 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9411
hERG inhibition (predictor II)	Non-inhibitor	0.9281

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	splash10-006t-0790000000-1c7572aeca7467120afa
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0002-0090000000-f15305003b9432e4a140
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0002-0090000000-4238be1fee0092f9d560
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0002-0090000000-b5749ff840be3eb05866
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0002-0090000000-cb335f6b27ab482ab074
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0a4i-0390000000-5581bd044894a3047c4e
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0aba-1790000000-050d4a14e8a71a11fe3e
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	171.1738322	predicted	DarkChem Lite v0.1.0
[M-H]-	156.19629	predicted	DeepCCS 1.0 (2019)
[M+H]+	171.9275322	predicted	DarkChem Lite v0.1.0
[M+H]+	158.57237	predicted	DeepCCS 1.0 (2019)
[M+Na]+	171.6319322	predicted	DarkChem Lite v0.1.0
[M+Na]+	164.64745	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. Xanthine dehydrogenase/oxidase

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

General Function

Xanthine oxidase activity

Specific Function

Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. Ha...

Gene Name

XDH

Uniprot ID

P47989

Uniprot Name

Xanthine dehydrogenase/oxidase

Molecular Weight

146422.99 Da

References

1. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [Article]

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Drug created at June 13, 2005 13:24 / Updated at February 03, 2022 21:01