Xanthine oxidoreductase (XOR) belongs to the group of molybdenum-containing hydroxylases involved in the oxidative metabolism of purines. Xanthine oxidoreductase is a key enzyme in purine degradation. It catalyzes the oxidation of hypoxanthine to xanthine and the oxidation of xanthine to uric acid. Xanthine oxidoreductase contributes to the generation of reactive oxygen species.
Topiroxostat, also termed FYX-051, is a XOR inhibitor with IC50 value of 5.3 nM in an in vitro assay[3]. Steady-state kinetics study showed that topiroxostat behaved as a competitive-type inhibitor with a Ki value of 5.7 × 10 nM[4].
Oral administration of Topiroxostat at doses ranging in 0.03-1mg/kg dose-dependently decreased serum urate levels in oxonate-induced hyperuricemic rats, with ED50 values of 0.15 mg/kg, 0.25 mg/kg and 0.70 mg/kg at 1h, 6h, and 12h[4]. Oral administration of Topiroxostat at doses of 0.1, 0.3, 1 and 3 mg/kg/day for 4 weeks dose-dependently decreased the urinary albumin excretion, inhibited plasma XOR activity in diabetic mice model[5].
Topiroxostat/托匹司他 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human kidney proximal tubule epithelial cells (HK-2 cells)
5 or 10 µM
1 hour
To investigate the effects of XO inhibition on LDL-induced oxidative stress and cholesterol synthesis. Results showed that TP reduced LDL-induced cellular ROS, similar to the positive control NAC.
Int J Mol Sci. 2020 Oct 9;21(20):7444
Topiroxostat/托匹司他 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
High HPRT activity –Uox knockout mice
Dietary administration
1 mg/kg
Once daily for 7 days
Evaluate the effect of topiroxostat on urate metabolism, significantly reduced plasma urate levels and urinary urate/creatinine ratio without affecting HPRT activity
Br J Pharmacol. 2020 May;177(10):2274-2285
Rats
SU5416/hypoxia/normoxia-induced pulmonary hypertension model
Admixed in diet
1 mg/kg
Started from the day of SU5416 injection to week 5
To investigate the effect of Topiroxostat on pulmonary arterial hypertension, results showed that Topiroxostat significantly reduced lung XOR activity in PAH rats, with no effects on increase in right ventricular systolic pressure, arterial elastance, and occlusive lesions.
J Am Heart Assoc. 2021 Dec 7;10(23):e022712
ApoE knockout mice
Uninephrectomy-induced chronic kidney disease (CKD) model
Oral gavage
1 mg/kg/day
Once daily for 4 weeks
To investigate the effects of XO inhibition on high-cholesterol diet-induced renal dysfunction. Results showed that TP attenuated hypercholesterolemia-associated renal dysfunction, reduced kidney cholesterol accumulation and oxidative stress.
Int J Mol Sci. 2020 Oct 9;21(20):7444
C57BL/6J mice
Nonobese NAFLD/NASH model
Drug-admixed food method
1 mg/kg/day
Once daily for 3 weeks
To investigate the inhibitory effect of topiroxostat on vascular neointima formation in NAFLD/NASH mice. Results showed that topiroxostat significantly suppressed plasma XOR activity and attenuated neointima formation induced by carotid artery ligation.
JCI Insight. 2021 Sep 8;6(17):e144762
Rats
Renal ischemia-reperfusion injury model
Oral
10 mg/kg
Single dose, 60 min before surgery
To evaluate the protective effects of Topiroxostat on renal ischemia-reperfusion injury, results showed that Topiroxostat increased renal concentrations of high-energy phosphates and reduced depletion of adenine compounds.
Mol Med. 2019 Aug 22;25(1):40
Mice
Diabetic obese model
Oral
3 mg/kg/day
Once daily for 4 weeks
To investigate the effect of topiroxostat on body weight. Results showed that topiroxostat suppressed weight gain without affecting food intake, decreased plasma uric acid and liver XOR activity, and increased hepatic hypoxanthine and plasma ketone bodies and free fatty acids.
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