Novel Alkylglycosides with Anti-Diabetic Activity

描述(申请人提供)：1型和2型糖尿病患者肝脏和肌肉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，对维持血糖的动态平衡尤为重要，并为抗糖尿病药物的作用提供了一个有吸引力的靶点，直到最近才被充分开发。本建议的主要目的是设计、合成和纯化一系列新型烷基麦芽糖苷，并在体内外测试这些化合物作为糖原合成的人工引导物的能力，从而增加葡萄糖进入肝糖原的处置，从而降低血糖水平。 O-烷基麦芽糖苷作为糖原生物合成酶、糖原合成酶和糖原合成酶进行葡萄糖转移的受体的能力将在体外测定小鼠肝脏的可溶性和颗粒性部分。那些活性最高的化合物作为这些酶的底物将被转化为S-烷基麦芽糖苷，它也将在体外作为糖原生物合成酶的葡萄糖受体底物进行测试。体外酶法筛选过程中活性最高的0-和/或S-烷基麦芽糖苷将在肥胖-高血糖(ob/ob)2型糖尿病小鼠模型上进行体内口服测试，以了解它们降低这些动物的血糖水平和改善糖耐量的能力。 这一阶段的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.烷基麦芽糖苷的分离纯化及性质 3.作为糖原生物合成酶底物的烷基麦芽糖苷的检测 4.建立肥胖/肥胖小鼠模型，观察最有效的O-和/或S烷基麦芽糖苷对小鼠血糖和糖耐量的影响。

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.