Osada Y, Tsuchimoto M, Fukushima H, Takahashi K, Kondo S, Hasegawa M, Komoriya K
Teijin Institute for Bio-medical Research, Tokyo, Japan.
Eur J Pharmacol. 1993 Sep 14;241(2-3):183-8. doi: 10.1016/0014-2999(93)90201-r.
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.
我们研究了一种新合成的黄嘌呤氧化酶/黄嘌呤脱氢酶抑制剂TEI-6720（2-(3-氰基-4-异丁氧基苯基)-4-甲基-5-噻唑羧酸）的黄嘌呤氧化酶/黄嘌呤脱氢酶抑制活性和降尿酸作用，并在啮齿动物中将其效果与别嘌醇进行了比较。结果发现，TEI-6720可抑制牛乳黄嘌呤氧化酶以及小鼠肝脏和大鼠肝脏中的黄嘌呤氧化酶/黄嘌呤脱氢酶，其IC50值分别为1.4、1.8和2.2 nM。对于牛乳黄嘌呤氧化酶，TEI-6720表现出混合型抑制作用，其Ki值为0.7 nM。TEI-6720在正常小鼠和大鼠中显示出持久的尿酸降低活性。我们评估了TEI-6720对尿酸酶抑制剂氧嗪酸钾（250 mg/kg皮下注射，在测试药物前1小时）诱导的高尿酸血症的降尿酸作用，并测量了大鼠血清中尿囊素和尿酸盐的总摩尔浓度。口服TEI-6720和别嘌醇在给氧嗪酸钾预处理的大鼠给药2小时后具有降尿酸作用，其ED50值分别为1.5和5.0 mg/kg。两种化合物还降低了大鼠尿酸和尿囊素的总摩尔浓度。TEI-6720和别嘌醇的口服ED50值分别为2.1和6.9 mg/kg。这些结果表明，TEI-6720可能对高尿酸血症的治疗有用。
