Hypouricemic effect of the novel xanthine oxidase inhibitor, TEI-6720, in rodents.
We investigated the xanthine oxidase/xanthine dehydrogenase inhibitory activity and hypouricemic effect of a newly synthesized xanthine oxidase/xanthine dehydrogenase inhibitor, TEI-6720, 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazole-carboxylic acid, and compared its effects with those of allopurinol in rodents. TEI-6720 was found to inhibit bovine milk xanthine oxidase, and mouse liver and rat liver xanthine oxidase/xanthine dehydrogenase with IC50 values of 1.4, 1.8 and 2.2 nM, respectively. On bovine milk xanthine oxidase, TEI-6720 exhibited mixed-type inhibition and the Ki value was 0.7 nM. TEI-6720 displayed prolonged urate-lowering activity in normal mice and rats. We evaluated the hypouricemic effect of TEI-6720 on hyperuricemia induced by the uricase inhibitor, potassium oxonate (250 mg/kg s.c., 1 h before the test drugs), and measured the total molarity of both serum allantoin and urate in rats. Oral TEI-6720 and allopurinol had a hypouricemic effect 2 h after their administration to oxonate-pretreated rats with ED50 values of 1.5 and 5.0 mg/kg, respectively. Both compounds also reduced the combined molarity of uric acid and allantoin in rats. The ED50 values of TEI-6720 and allopurinol were 2.1 and 6.9 mg/kg p.o., respectively. These results suggest that TEI-6720 may be useful for the treatment of hyperuricemia.
Osada
Y
Y
Teijin Institute for Bio-medical Research, Tokyo, Japan.
Tsuchimoto
M
M
Fukushima
H
H
Takahashi
K
K
Kondo
S
S
Hasegawa
M
M
Komoriya
K
K
D000481:Allantoin / Q000097:blood; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D000069465:Febuxostat; D006074:Gout Suppressants / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology*; D014527:Uric Acid / Q000097:blood; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
D006074:Gout Suppressants; D013844:Thiazoles; D000069465:Febuxostat; D014527:Uric Acid; D000481:Allantoin; D000493:Allopurinol; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase