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Also known as: 577778-58-6, Fyx 051, Fyx-051, 4-(5-pyridin-4-yl-1h-1,2,4-triazol-3-yl)pyridine-2-carbonitrile, Topiroxostat [inn], 2-pyridinecarbonitrile, 4-[5-(4-pyridinyl)-1h-1,2,4-triazol-3-yl]-

Molecular Formula

C₁₃H₈N₆

Molecular Weight

248.24 g/mol

InChI Key

UBVZQGOVTLIHLH-UHFFFAOYSA-N

FDA UNII

0J877412JV

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 [DB00437] and [DB05262], and non-purine agents which includes topiroxostat. While [DB00437] 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 [DB00437] 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. Approved for therapeutic use in Japan since 2013, topiroxostat is marketed under the name Topiloric and Uriadec and is orally administered twice daily.

1 2D Structure

Topiroxostat

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

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

2.1.2 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)

2.1.3 InChI Key

UBVZQGOVTLIHLH-UHFFFAOYSA-N

2.1.4 Canonical SMILES

C1=CN=CC=C1C2=NC(=NN2)C3=CC(=NC=C3)C#N

2.2 Other Identifiers

2.2.1 UNII

0J877412JV

2.3 Synonyms

2.3.1 MeSH Synonyms

1. 4-(5-pyridin-4-yl-1h-(1,2,4) Triazol-3-yl)pyridine-2-carbonitrile

2. Fyx-051

2.3.2 Depositor-Supplied Synonyms

1. 577778-58-6

2. Fyx 051

3. Fyx-051

4. 4-(5-pyridin-4-yl-1h-1,2,4-triazol-3-yl)pyridine-2-carbonitrile

5. Topiroxostat [inn]

6. 2-pyridinecarbonitrile, 4-[5-(4-pyridinyl)-1h-1,2,4-triazol-3-yl]-

7. 5-(2-cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole

8. Chembl1078685

9. 4-(5-(pyridin-4-yl)-1h-1,2,4-triazol-3-yl)picolinonitrile

10. 4-(5-(pyridin-4-yl)-1h-1,2,4-triazol-3-yl)pyridine-2-carbonitrile

11. Mfcd17167057

12. 0j877412jv

13. 4-[5-(pyridin-4-yl)-1h-1,2,4-triazol-3-yl]pyridine-2-carbonitrile

14. Topiloric

15. Uriadec

16. 4-(3-(pyridin-4-yl)-1h-1,2,4-triazol-5-yl)picolinonitrile

17. Unii-0j877412jv

18. Uriadec (tn)

19. Topiroxostat (jan/inn)

20. Topiroxostat [mi]

21. Topiroxostat [jan]

22. Schembl860420

23. Topiroxostat [who-dd]

24. Schembl18056618

25. Gtpl10592

26. Dtxsid80206462

27. Bcp09957

28. Ex-a1197

29. 4-(5-pyridin-4-yl-1h-(1,2,4) Triazol-3-yl)pyridine-2-carbonitrile

30. 4-[5-(4-pyridyl)-1h-1,2,4-triazol-3-yl]pyridine-2-carbonitrile

31. Bdbm50267750

32. Bdbm50311275

33. S3719

34. Zinc13536586

35. 4-[5-pyridin-4-yl-1h-[1,2,4]triazol-3-yl]-pyridine-2-carbonitrile

36. Akos026750465

37. Akos026751485

38. (fyx-051)"

39. Ccg-266938

40. Cs-2033

41. Db01685

42. Ncgc00378610-01

43. Ncgc00378610-02

44. Ac-30740

45. As-56359

46. Hy-14874

47. Sy116097

48. Ft-0700966

49. A14144

50. D09786

51. Q15725832

2.4 Create Date

2005-11-29

3 Chemical and Physical Properties

Molecular Formula	C₁₃H₈N₆
Molecular Weight	248.24 g/mol
XLogP3	1.2
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	2
Exact Mass	248.08104428 g/mol
Monoisotopic Mass	248.08104428 g/mol
Topological Polar Surface Area	91.1 Å²
Heavy Atom Count	19
Formal Charge	0
Complexity	344
Isotope Atom Count	0
Defined Atom Stereocenter Count	0
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

Indicated for the treatment of gout and hyperurcemia in Japan.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Topiroxostat reduces the synthesis of uric acid by competitively inhibiting xanthine oxidase in a selective and time-dependent manner. 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.

5.2 MeSH Pharmacological Classification

Enzyme Inhibitors

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)

5.3 Absorption, Distribution and Excretion

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. The oral bioavailability in male rats was 69.6% after oral administration of a single dose of 1mg/kg.

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.

Volume of Distribution

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

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.

5.4 Metabolism/Metabolites

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. 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. 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.

FYX-051 has known human metabolites that include (2S,3S,4S,5R)-6-[3-(2-cyanopyridin-4-yl)-5-pyridin-4-yl-1,2,4-triazol-1-yl]-3,4,5-trihydroxyoxane-2-carboxylic acid and 4-[2-[(3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxyoxan-2-yl]-5-pyridin-4-yl-1,2,4-triazol-3-yl]pyridine-2-carbonitrilium.

S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560

5.5 Biological 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.

5.6 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. 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. It also forms hydrogen bonds with molybdenum (VI) ion, suggesting that it has multiple inhibition modes to xanthine oxidase. 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. 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.