| Identification | Back Directory | [Name]
FYX 051 | [CAS]
577778-58-6 | [Synonyms]
FYX 051
CS-1334
Uriadec.
inonitriL
Toby Starr
Topiroxosta
Topiroxostat
Topicast impurity
4-(3-(Pyridin-4-yL
[14C]-Topiroxostat
Topiroxostat,FYX-051
Topiroxostat impurty
Topiroxostat. trade names Topiloric
3-(3-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole
5-(2-Cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole
Topiroxostat C13H8N6 high quality Cas number：577778-58-6
4-(3-(Pyridin-4-yl)-1H-1,2,4-triazol-5-yl)picolinonitrile
4-[5-(4-Pyridyl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile
4-(5-pyridin-4-yl-1H-1,2,4-triazol-3-yl)pyridine-2-carbonitrile
4-[5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile
2-Pyridinecarbonitrile, 4-[5-(4-pyridinyl)-1H-1,2,4-triazol-3-yl]-
2-Pyridinecarbonitrile, 4-[3-(4-pyridinyl)-1H-1,2,4-triazol-5-yl]-
Topiroxostat 5-(2-Cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole
FYX-051; FYX051; FYX 051; TOPIROXOSTAT. TRADE NAMES TOPILORIC; URIADEC.
Factory supply Topiroxostat Cas 577778-58-6 with high quality and best price | [EINECS(EC#)]
1592732-453-0 | [Molecular Formula]
C13H8N6 | [MDL Number]
MFCD28384402 | [MOL File]
577778-58-6.mol | [Molecular Weight]
248.243 |
| Chemical Properties | Back Directory | [Boiling point ]
594.7±60.0 °C(Predicted) | [density ]
1.45±0.1 g/cm3(Predicted) | [storage temp. ]
Store at -20°C | [solubility ]
DMSO : 23.5 mg/mL (94.67 mM; Need ultrasonic and warming) | [form ]
Powder | [pka]
7.47±0.10(Predicted) | [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) | [InChIKey]
UBVZQGOVTLIHLH-UHFFFAOYSA-N | [SMILES]
C1(C#N)=NC=CC(C2NN=C(C3C=CN=CC=3)N=2)=C1 | [Uses]
Topiroxostat (577778-58-6), a selective xanthine oxidoreductase inhibitor, is used in Japan for the treatment of hyperuricemic patients with or without gout. In terms of the effectiveness of topiroxostat in lowering serum urate levels, the dose–response relationship has been evaluated; however, it remains to be verified. A randomized, multi-center, double-blinded study of topiroxostat was performed for Japanese hyperuricemic patients with or without gout. During the 16-week study, 157 Japanese hyperuricemic patients with or without gout were randomly assigned to receive a placebo, topiroxostat at 120 or 160 mg/day, or allopurinol at 200 mg/day. The primary endpoint of this study was to determine the lowering rate of serum uric acid levels compared to those of baseline at the end of administration. A dose–response relationship (regarding decreases in the serum urate levels) was confirmed for the placebo and topiroxostat at 120 and at 160 mg/day. Moreover, at the end of administration, the lowering rate of serum urate levels was determined to be ?44.8% in the topiroxostat 160-mg/day group. No significant difference in the incidence of adverse events was observed among all groups, including the allopurinol group. The serum urate-lowering effect of topiroxostat was found to have a dose–response relationship in Japanese hyperuricemic patients with or without gout.
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| Hazard Information | Back Directory | [Description]
Topiroxostat (577778-58-6) is an orally-administered, non-purine, selective
xanthine oxidase (XO) inhibitor developed for the treatment of
hyperuricemia specifically for patients with gout in Japan. The
drug was discovered and developed by Fuji Yakuhin. In contrast
to conventional XO inhibitors such as febuxostat, topiroxostat
interacts with key amino acid residues of the solvent channel.
| [Chemical Properties]
Topiroxostat is soluble in organic solvents such as DMSO and dimethyl formamide (DMF). The solubility of topiroxostat in these solvents is approximately 10 and 20 mg/ml, respectively. | [Biological Activity]
Topiroxostat(577778-58-6) is an inhibitor of xanthine oxidoreductase (IC50 = 5.3 nM), an enzyme that converts xanthine to urate. Formulations containing topiroxostat are effective in vivo, lowering urate levels in the serum of patients with hyperuricemia. In rats, but not primates, topiroxostat treatment results in the formation of xanthine crystals, resulting in nephritis. Topiroxostat also inhibits ATP-binding cassette transporter G2 (ABCG2; IC50 = 0.18 μM), a high-capacity urate transporter that functions in both renal and extrarenal urate secretion.
| [Pharmacology]
Topiroxostat is a novel inhibitor of xanthine oxidase, and is postulated to exert a renoprotective effect. Puromycin aminonucleoside nephrosis (PAN) is a rat model of minimal change nephrotic syndrome. In this study, we examined whether topiroxostat ameliorates the kidney injury in PAN rats that was induced by a single intraperitoneal injection of PA (100mg/kg body weight). Rats were divided into four groups: control rats, PAN rats, control rats treated with topiroxostat (1.0mg/kg/day), and PAN rats treated with topiroxostat. Topiroxostat significantly reduced the amount of uric acid in the kidney cortex, while serum UA concentration remained unaffected by this treatment. Urinary protein excretion decreased significantly on day 10 in PAN rats upon topiroxostat treatment. Podocyte injury in PAN rats, as indicated by the reduction in WT‐1‐positive cell numbers and podocin immunoreactivity and foot process effacement, was partially yet significantly alleviated with topiroxostat treatment. In the kidney cortex, the increase in oxidative stress markers such as nitrotyrosine and 8‐hydroxy‐2‐deoxyguanosine (8‐OHdG) and the enhanced expressions of xanthine oxidase and NADPH oxidase 4 (NOX4) in PAN rats were significantly ameliorated by topiroxostat. Using cultured podocytes NOX4 expression was upregulated by adding 12mg/dL UA into the culture medium. These results suggest that topiroxostat ameliorates proteinuria and kidney injury in PAN rats by lowering oxidative stress and tissue UA concentration. The renoprotective effects of topiroxostat could be attributed to its potential to inhibit xanthine oxidase and NOX4 in concert with suppression of intracellular UA production. Abstract : Topiroxostat ameliorates proteinuria and renal injury independently of serum UA level in PAN‐induced nephrotic rats. Topiroxostat exerts a renoprotective effect owing to its antioxidant effects and property to lower UA levels in the kidney cortex. | [Clinical Use]
Topiroxostat(577778-58-6), a novel XO inhibitor, ameliorated proteinuria in association with podocyte injury markers such as decrease in WT-1 and podocin expressions and foot process effacement on electron microscope.
| [Synthesis]
The synthesis commenced with the reaction of two commercially
available components, nitrile oxide 177 and isonicotinohydrazide
(178). Condensation of these two subunits in the
presence of sodium methoxide followed by acidic quench gave rise
to 1,2,4-triazole 179 in 89% yield. Next, utilization of the N-oxide
for installation of the nitrile functionality was required to furnish
the drug, but it is interesting to note that this step has been the
subject of study by Yamamoto and co-workers at Tohoku
University in Japan. Although the process preparation describes
the formation of the drug using sodium cyanide and dimethylcarbamoyl
chloride followed by isolation through a salt formation/
freebasing process to deliver topiroxostat (XXIII) in 66% yield,
Yamamoto has described this same sequence using zinc cyanide
and tosylate salt formation (freebasing of the drug was not
attempted).
| [Carcinogenicity]
Carcinogenicity was evaluated in 2-year oral dose studies in mice and rats. Tumors developed in both animal species (mice, mammary adenocarcinoma; rats, transitional cell papilloma/papillary carcinoma in the kidney and bladder, transitional cell carcinoma in the ureter, renal cell carcinoma and angiosarcoma in the kidney, follicular cell adenoma in the thyroid), secondary to chronic renal impairment probably due to xanthine crystal deposition. Comparison of the exposure (AUC)7 to unchanged topiroxostat at the non-carcinogenic doses in mice and rats and at the maximum recommended clinical dose yielded a safety margin of <1-fold in both animal species. However, the applicant has considered that the observed tumorigenesis is not relevant to humans because xanthine crystal deposition is pronounced in rodents in comparison with other animal species including humans. | [storage]
Store at -20°C |
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