Na(+)-glucose cotransporter (SGLT) inhibitors as antidiabetic agents. 4. Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives substituted on the B ring.
Na(+)-glucose cotransporter (SGLT) inhibitors as antidiabetic agents. 4. Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives substituted on the B ring.
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DOI：
10.1021/jm990175n
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发表时间：
1999-12
影响因子：
7.3
通讯作者：
K. Tsujihara;M. Hongu;Kunio Saito;Hiroyuki Kawanishi;Kayoko Kuriyama;Mamoru Matsumoto;A. Oku;
中科院分区：
文献类型：
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作者：
K. Tsujihara;M. Hongu;Kunio Saito;Hiroyuki Kawanishi;Kayoko Kuriyama;Mamoru Matsumoto;A. Oku;
在Na(+)-葡萄糖共转运体(SGLT)抑制剂作为降糖药物的研究中，我们合成了一系列新的B环取代的4‘-脱羟基根苷类化合物，并评价了它们对大鼠尿糖排泄的影响。在4‘-位引入少量烷基可提高活性，其中3-(benzo¿bfuran-5-yl)-2’，6‘-dihydroxy-4’-methylpropiophenone 2‘-O-β-D-吡喃葡萄糖苷(4)的作用最强。为了克服β-葡萄糖苷酶在消化道对化合物4的水解作用，对化合物4的葡萄糖部分上的羟基进行了修饰。3种前药(5、42和55)的口服药效高于母体化合物4，最终3-(benzo¿bfuran-5-yl)-2‘，6’-dihydroxy-4‘-methylpropiophenone 2’-O-(6-O-methoxycarbonyl-beta-D-glucopyranoside)(5)被选为新的有希望的候选药物。化合物5主要被肝酯酶代谢为活性形式(4)，其抑制SGLT的能力约为5的10倍。在db/db小鼠的口服葡萄糖耐量试验中，化合物5呈剂量依赖性地抑制血糖水平的升高。单次应用5可降低糖尿病KK-A(Y)小鼠的高血糖，同时增加尿糖排泄。此外，化合物5抑制KK-A(Y)小鼠血糖水平的升高，但即使在禁食条件下也不能将其降低到正常水平以下。此外，长期服用5 mg/kg可剂量依赖性地降低KK-A(Y)小鼠的高血糖和糖化血红蛋白。这些药理数据有力地表明化合物5在治疗NIDDM方面具有潜在的治疗潜力。
In our studies of Na(+)-glucose cotransporter (SGLT) inhibitors as antidiabetic agents, a series of novel 4'-dehydroxyphlorizin derivatives substituted on the B ring was prepared and their effects on urinary glucose excretion were evaluated in rats. Introduction of only a small alkyl group at the 4'-position increased the activity, and 3-(benzo¿bfuran-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-beta-D-glucopyranoside (4) showed the most potent effect. To overcome hydrolysis of compound 4 by beta-glucosidase in the digestive tract, the OH groups on the glucose moiety of compound 4 were modified. Three prodrugs (5, 42, and 55) were more potent than the parent compound 4 by oral administration, and finally 3-(benzo¿bfuran-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-(6-O-methoxycarbonyl-beta-D-glucopyranoside) (5) was selected as a new promising candidate. Compound 5 was metabolized mainly by liver esterase to the active form (4), which was about 10 times more potent than 5 in inhibiting SGLT. In oral glucose tolerance test in db/db mice, compound 5 dose-dependently suppressed the elevation of glucose levels. Single administration of 5 reduced hyperglycemia concurrently with increase of glucose excretion into urine in diabetic KK-A(y) mice. Furthermore, compound 5 suppressed the elevation of blood glucose levels but did not lower it below the normal level even in fasted conditions in KK-A(y) mice. Additionally, long-term treatment with 5 dose-dependently reduced hyperglycemia and HbA1c in KK-A(y) mice. These pharmacological data strongly suggest that compound 5 has a therapeutic potential in the treatment of NIDDM.