577778-58-6 Usage
Description
FYX 051, also known as Topiroxostat, 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. It interacts with key amino acid residues of the solvent channel, making it a promising pharmaceutical candidate for managing hyperuricemia and gout.
Uses
Used in Pharmaceutical Industry:
FYX 051 is used as a selective xanthine oxidase inhibitor for the treatment and management of hyperuricemia and gout. By inhibiting the enzyme xanthine oxidase, which regulates purine metabolism, FYX 051 results in an efficacious reduction of serum urate levels, providing relief to patients suffering from gout.
Used in Drug Delivery Systems:
FYX 051 is used in drug delivery systems to improve its solubility and bioavailability. FYX 051 is soluble in organic solvents such as DMSO and dimethyl formamide (DMF), with solubility levels of approximately 10 and 20 mg/ml, respectively. This characteristic allows for the development of novel drug delivery systems that can enhance the efficacy and therapeutic outcomes of FYX 051 in treating hyperuricemia and gout.
Biological Activity
Topiroxostat 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, 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.
Check Digit Verification of cas no
The CAS Registry Mumber 577778-58-6 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 5,7,7,7,7 and 8 respectively; the second part has 2 digits, 5 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 577778-58:
(8*5)+(7*7)+(6*7)+(5*7)+(4*7)+(3*8)+(2*5)+(1*8)=236
236 % 10 = 6
So 577778-58-6 is a valid CAS Registry Number.
577778-58-6Relevant articles and documents
Preparation method of medicine for treating chronic hyperuricemia
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, (2021/04/14)
The invention discloses a preparation method of a medicine for treating chronic hyperuricemia. The method comprises the following steps: using methyl 2-cyanoisonicotinate and 4-cyanopyridine as initial raw materials, and carrying out hydrazinolysis reaction, condensation reaction, cyclization reaction and purification to obtain topiroxostat. On one hand, by using a hydrochloric acid alcohol solution, the energy consumption of the process is reduced, and the problem of poor safety is improved; and on the other hand, topiroxostat hydrochloride is refined and concentrated in alcohol water and then subjected to a salt dissolving process, so that the solubility of the topiroxostat in an alkaline solution is increased, the problem that chloride exceeds the standard is preliminarily solved, the salt dissolving process is more thorough, and the reaction proceeding degree is increased. Finally, in the purification process, the amount of chlorides in the product is further reduced by a method of hot melting the crude product in alcohol water, and the product quality is ensured; and the purity of the product is improved by selecting a purification solvent.
One-pot method for synthesizing Topiroxostat
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Paragraph 0019; 0020, (2017/01/02)
The invention discloses a one-pot method for synthesizing Topiroxostat. The one-pot method comprises the following steps: dissolving 2-cyano methyl isonicotinate into a solvent, reacting with hydrazine hydrate to generate an intermediate 2-cyanoisoniazide, then adding alkali for reaction in the same reactor, then adding 4-cyanopyridine to form a ring, and finally purifying to obtain the Topiroxostat. The one-pot method is short in technological process, simple in operation, high in raw material utilization rate and low in production cost, and has higher production and practical value.
