MB06322 (CS-917): A potent and selective inhibitor of fructose 1,6-bisphosphatase for controlling gluconeogenesis in type 2 diabetes
MB06322 (CS-917): A potent and selective inhibitor of fructose 1,6-bisphosphatase for controlling gluconeogenesis in type 2 diabetes
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DOI：
10.1073/pnas.0502983102
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发表时间：
2005-05-31
影响因子：
11.1
通讯作者：
Lipscomb, WN
中科院分区：
文献类型：
--
作者：
Erion, MD;van Poelje, PD;Lipscomb, WN
在2型糖尿病中，肝脏通过葡萄糖生成（GNG）途径产生过量的葡萄糖，因此部分导致该疾病的葡萄糖水平升高。为了寻找安全有效的GNG抑制剂，我们靶向果糖1，6-二磷酸酶（FBPase）的AMP结合位点。AMP结合位点的亲水性及其在代谢途径中酶的变构调节的广泛应用历史上使得发现适合于药物开发的AMP模拟物变得困难。通过使用基于结构的药物设计策略，我们发现了一系列模拟AMP但结构相似性很小的化合物。先导化合物MB 05032对人FBPase表现出高效力和特异性。通过使用双酰胺酯前药MB 06322（CS-917）实现MB 05032的口服递送，其通过酯酶和磷酰胺酶的作用在两个步骤中转化为MB 05032。MB 06322抑制大鼠肝细胞中多种GNG底物和雄性Zucker糖尿病肥胖大鼠中碳酸氢盐的葡萄糖生成。对肝脏GNG途径中间体的分析证实了FBPase是作用位点。Zucker糖尿病肥胖大鼠经口给予MB 06322导致血糖水平呈剂量依赖性降低，与胰岛素水平和营养状况无关。发生葡萄糖降低，无低血糖体征或血浆乳酸盐或甘油三酯水平显著升高。研究结果表明，有效和特异性的FBPase抑制剂代表了一类有潜力通过抑制GNG治疗2型糖尿病的药物。
In type 2 diabetes, the liver produces excessive amounts of glucose through the gluconeogenesis (GNG) pathway and consequently is partly responsible for the elevated glucose levels characteristic of the disease. In an effort to find safe and efficacious GNG inhibitors, we targeted the AMP binding site of fructose 1,6-bisphosphatase (FBPase). The hydrophilic nature of AMP binding sites and their widespread use for allosteric regulation of enzymes in metabolic pathways has historically made discovery of AMP mimetics suitable for drug development difficult. By using a structure-based drug design strategy, we discovered a series of compounds that mimic AMP but bear little structural resemblance. The lead compound, MB05032, exhibited high potency and specificity for human FBPase. Oral delivery of MB05032 was achieved by using the bisamidate prodrug MB06322 (CS-917), which is converted to MB05032 in two steps through the action of an esterase and a phosphoramidase. MB06322 inhibited glucose production from a variety of GNG substrates in rat hepatocytes and from bicarbonate in male Zucker diabetic fatty rats. Analysis of liver GNG pathway intermediates confirmed FBPase as the site of action. Oral administration of MB06322 to Zucker diabetic fatty rats led to a dose-dependent decrease in plasma glucose levels independent of insulin levels and nutritional status. Glucose lowering occurred without signs of hypoglycemia or significant elevations in plasma lactate or triglyceride levels. The findings suggest that potent and specific FBPase inhibitors represent a drug class with potential to treat type 2 diabetes through inhibition of GNG.