Novel Alkylglycosides with Anti-Diabetic Activity

具有抗糖尿病活性的新型烷基糖苷

• 批准号: 6935715
• 负责人: Nicholas Cairns
• 金额: $ 27.67万
• 依托单位: COMBINIX, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6935715
• 关键词: blood glucose; drug screening /evaluation; genetic strain; glucose tolerance; glycogenesis; glycogenolysis; glycosides; hypoglycemic agents; laboratory mouse; liver metabolism; maltose; noninsulin dependent diabetes mellitus; obesity

DESCRIPTION (provided by applicant): Glycogen metabolism and its regulation are abnormal in liver and muscle in both Type 1 and Type 2 diabetes mellitus. Liver glycogen metabolism is particularly important to maintaining blood glucose homeostasis through regulating the uptake and release of glucose and provides an attractive target for the action of antidiabetic drugs which until recently has not been fully exploited. The principal objective of this proposal is to design, synthesize and purify a series of novel alkylmaltosides and to test these compounds in vitro and in vivo for their ability to serve as artificial primers for glycogen synthesis that can increase glucose disposal into liver glycogen and thereby lower blood glucose levels. The ability of the O-alkylmaltosides to serve as acceptors for glucose transfer by the glycogen biosynthetic enzymes glycogenin and glycogen synthase will be determined in soluble and particulate fractions of mouse liver in vitro. Those compounds with the most activity as substrates for these enzymes will be converted to S-alkylmaltosides which will also be tested in vitro as glucose acceptor substrates for the glycogen biosynthetic enzymes. The most active 0- and/or S-alkylmaltosides in the in vitro enzymatic screening procedure will be tested orally in vivo in the obese-hyperglycemic (ob/ob) mouse model of type 2 diabetes for their ability to lower blood glucose levels and improve glucose tolerance in these animals. There are four specific aims in this phase I proposal: 1. Design and Synthesis of a Series of Novel Alkylmaltosides 2. Purification and Characterization of the Alkylmaltosides 3. Testing of the Alkylmaltosides as Substrates for the Glycogen Biosynthetic Enzymes 4. Determine the Effects of the Most Active O- and/or S-Alkylmaltosides on Blood Glucose and Glucose tolerance in the ob/ob Mouse Model.

描述（申请人提供）：1型和2型糖尿病的肝脏和肌肉中糖原代谢及其调节均异常。肝糖原代谢通过调节葡萄糖的摄取和释放来维持血糖稳态特别重要，并为抗糖尿病药物的作用提供了一个有吸引力的靶点，但直到最近尚未得到充分利用。该提案的主要目标是设计、合成和纯化一系列新型烷基麦芽糖苷，并在体外和体内测试这些化合物作为糖原合成人工引物的能力，从而增加葡萄糖转化为肝糖原的能力，从而降低血糖水平。 O-烷基麦芽糖苷作为糖原生物合成酶糖原蛋白和糖原合成酶进行葡萄糖转移的受体的能力将在体外小鼠肝脏的可溶性和颗粒级分中测定。作为这些酶的底物的最具活性的那些化合物将被转化为S-烷基麦芽糖苷，其也将作为糖原生物合成酶的葡萄糖受体底物在体外进行测试。体外酶筛选程序中活性最高的 0- 和/或 S-烷基麦芽糖苷将在 2 型糖尿病肥胖高血糖 (ob/ob) 小鼠模型中进行体内口服测试，以了解其降低这些动物血糖水平和改善糖耐量的能力。 第一阶段提案有四个具体目标： 1.一系列新型烷基麦芽糖苷的设计与合成 2. 烷基麦芽糖苷的纯化和表征 3. 烷基麦芽糖苷作为糖原生物合成酶底物的测试 4. 确定最活跃的 O-和/或 S-烷基麦芽糖苷对 ob/ob 小鼠模型中血糖和葡萄糖耐量的影响。