Topiroxostat

Topiroxostat(FYX-051) is a novel and potent xanthine oxidoreductase (XOR) inhibitor with IC50 value of 5.3 nM.IC50 value: 5.3 nM [1]Target: xanthine oxidoreductasein vitro: Steady-state kinetics study showed that FYX-051 initially behaved as a competitive-type inhibitor with a K(i) value of 5.7 × 10(-9) M, then after a few minutes it formed a tight complex with XOR via a Mo-oxygen-carbon atom covalent linkage, as reported previously [3].in vivo: FYX-051 exhibited a weak CYP3A4-inhibitory

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.

Take 3-(4-pyridyl)-5-(1-oxo-4-pyridinyl)-1, 2, 4-triazole p-toluenesulfonic acid 200g, 1.5 liters of DMF, and put it into a 3-liter three-necked flask.Add 120 ml of N, N-dimethylformyl chloride and stir at 5-10 ° C for 1 h.95 ml of trimethylsilyl cyanide was added dropwise, and the mixture was heated to 50 ° C.Stir the reaction for 2 h, until the temperature drops below 30 °C, 2N potassium carbonate solution was added dropwise to ph=7.5, stirred for 1 h, and filtered.It was obtained as a white solid, dried under vacuum at 55 ° C for 8 h, and obtained 10 g of topisita.The yield was 90.4percent.100 ml of anhydrous ethanol was put into a 500 ml reaction flask, and sliced sodium was added.Stir the reaction to prepare sodium ethoxide. After the reaction is complete, continue stirring for 1 hour. Add 10.8 g of 4-cyanopyridine, control the temperature at 25°C and stir for 1 hour. Add acetic acid to adjust the pH to 5.0.Stir for 10 minutes, Added 14 g of the intermediate 2-cyanoisonicotinic acid hydrazide prepared in Example 1, Start oil bath heating and circulation, reflux temperature 80 °C, reflux 7h, HPLC monitoring, When the raw material 2-cyanoisonicotinic acid hydrazide obtained by the peak area normalization method is ≤ 0.5percent, Stop the heating and circulation, release the heat transfer oil in the jacket, wait until the temperature drops below 30°C, feed and centrifuge, and filter cake is rinsed twice with 50 ml of ethanol. The filter cake was transferred to an enamel baking dish and dried under reduced pressure (80°C/The 4-cyano pyridine 11.5g (110mmol) dissolved in 500 ml methanol, then adding sodium methoxide 3.5g, stir to dissolve. Then add 2-cyano [...] 16.2g (100mmol), heating reflux for 8 hours. After the reaction, the separated solid filter, vacuum drying after washing with methanol, to obtain he holds a department 21.4g, yield 85.6percent, purity 99.5percent (HPLC).A solution of 1.04 g (10 mmol) of the compound of the formula (2) in 50 ml of methanol was added with sodium methoxide 50mg, stirring to dissolve. Then, 1.62 g (10 mmol) of the compound of the formula (3) 2-cyanoisoniazide was added and the mixture was refluxed for 10 hours Time. After the completion of the reaction, the precipitated solid was filtered off, washed with methanol and dried with vacuum chestnut to give a yellow powdery product Pisitatum (1.93 g, yield 78percent, HPLC purity (normalized method): 98.5percent.Compound (2) (2 g, 10 mmol) was added to 10 ml of ethanol and 10 ml of water, stirred at room temperature and dissolved. A solution of sodium hydrogencarbonate (sodium hydrogencarbonate 0.84 g in 10 ml of water) was added, and stirred at room temperature for 2 hours. The crystals were obtained by filtration, washed with water and ethanol, abd vacuum-dried to obtain 2.39 g of the objective compound as pale yellow crystals, i.e., the compound of the formula (1).

Topiroxostat, 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.

Molecular Weight:248.24
XLogP3:1.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:2
Exact Mass:248.08104428
Monoisotopic Mass:248.08104428
Topological Polar Surface Area:91.1
Heavy Atom Count:19
Complexity:344
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes