Identification

Name
Topiroxostat
Accession Number
DB01685  (EXPT01517)
Type
Small Molecule
Groups
Experimental
Description

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.

Structure
Thumb
Synonyms
  • 4-(5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl)pyridine-2-carbonitrile
External IDs
FYX-051
International/Other Brands
Topiloric (Fujiyakuhin Co.) / Uriadec (Sanwa Kagaku Kenkyusho Co.)
Categories
UNII
0J877412JV
CAS number
577778-58-6
Weight
Average: 248.2428
Monoisotopic: 248.081044286
Chemical Formula
C13H8N6
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

Pharmacology

Indication

Indicated for the treatment of gout and hyperurcemia in Japan.

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 [9]. 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, 9, 5, 6]. It also forms hydrogen bonds with molybdenum (VI) ion, suggesting that it has multiple inhibition modes to xanthine oxidase [9]. 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].

TargetActionsOrganism
UXanthine dehydrogenase/oxidaseNot AvailableHuman
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 [9]. The oral bioavailability in male rats was 69.6% after oral administration of a single dose of 1mg/kg [9].

Volume of distribution

The distribution of 14C-topiroxostat (20, 200, and 2000 ng/mL) in human blood cells was 6.7% to 12.8% [9].

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 [9].

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 [9].

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 [9].

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 [9].

Toxicity

Topiroxostat is not reported to be carcinogenic, genotoxic, or teratogenic [9]. 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 [9].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Topiroxostat.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Topiroxostat.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Topiroxostat.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Topiroxostat.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Topiroxostat.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Topiroxostat.
AbacavirAbacavir may decrease the excretion rate of Topiroxostat which could result in a higher serum level.
AbemaciclibTopiroxostat may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
AbirateroneThe metabolism of Abiraterone can be decreased when combined with Topiroxostat.
AcarboseAcarbose may decrease the excretion rate of Topiroxostat which could result in a higher serum level.
Food Interactions
Not Available

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. [PubMed:20952484]
  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. [PubMed:24448692]
  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. [PubMed:25501928]
  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. [PubMed:24214189]
  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. [PubMed:12421831]
  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. [PubMed:15148401]
  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. [PubMed:16914512]
  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. [PubMed:17761779]
  9. Pharmaceuticals and Medical Devices Agency (PMDA): Topiroxostat review [Link]
External Links
PubChem Compound
5288320
PubChem Substance
46508374
ChemSpider
4450517
BindingDB
50311275
ChEMBL
CHEMBL1078685
HET
FYX
Wikipedia
Topiroxostat
PDB Entries
1v97
MSDS
Download (23.9 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedBasic ScienceHyperuricemia1

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
PropertyValueSource
Water Solubility0.0779 mg/mLALOGPS
logP1.47ALOGPS
logP1.82ChemAxon
logS-3.5ALOGPS
pKa (Strongest Acidic)11.06ChemAxon
pKa (Strongest Basic)3.91ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area91.14 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity90.47 m3·mol-1ChemAxon
Polarizability25.39 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9553
Caco-2 permeable+0.5089
P-glycoprotein substrateNon-substrate0.8142
P-glycoprotein inhibitor INon-inhibitor0.914
P-glycoprotein inhibitor IINon-inhibitor0.9566
Renal organic cation transporterNon-inhibitor0.743
CYP450 2C9 substrateNon-substrate0.8646
CYP450 2D6 substrateNon-substrate0.8876
CYP450 3A4 substrateNon-substrate0.7258
CYP450 1A2 substrateInhibitor0.84
CYP450 2C9 inhibitorNon-inhibitor0.8298
CYP450 2D6 inhibitorNon-inhibitor0.9604
CYP450 2C19 inhibitorNon-inhibitor0.7387
CYP450 3A4 inhibitorInhibitor0.5479
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6341
Ames testAMES toxic0.6839
CarcinogenicityNon-carcinogens0.8822
BiodegradationNot ready biodegradable1.0
Rat acute toxicity1.8791 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9411
hERG inhibition (predictor II)Non-inhibitor0.9281
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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 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
Pyridyl-1,2,4-triazole / Heteroaromatic compound / 1,2,4-triazole / Triazole / Azole / Azacycle / Nitrile / Carbonitrile / Organic nitrogen compound / Organopnictogen compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
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. [PubMed:10592235]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
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
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Pharmaceuticals and Medical Devices Agency (PMDA): Topiroxostat review [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
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. Pharmaceuticals and Medical Devices Agency (PMDA): Topiroxostat review [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vitamin d 24-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
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
References
  1. Pharmaceuticals and Medical Devices Agency (PMDA): Topiroxostat review [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vitamin d3 25-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 performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Pharmaceuticals and Medical Devices Agency (PMDA): Topiroxostat review [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Current data supporting this enzyme inhibition is limited.
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Pharmaceuticals and Medical Devices Agency (PMDA): Topiroxostat review [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
Gene Name
UGT1A9
Uniprot ID
O60656
Uniprot Name
UDP-glucuronosyltransferase 1-9
Molecular Weight
59940.495 Da
References
  1. 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. [PubMed:17761779]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Pharmaceuticals and Medical Devices Agency (PMDA): Topiroxostat review [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Binder
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. Pharmaceuticals and Medical Devices Agency (PMDA): Topiroxostat review [Link]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. 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. [PubMed:28082903]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da
References
  1. Pharmaceuticals and Medical Devices Agency (PMDA): Topiroxostat review [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. Pharmaceuticals and Medical Devices Agency (PMDA): Topiroxostat review [Link]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 05:05