Pre-clinical studies to explore the therapeutic potential of insulin-degrading enzyme inhibitors

 描述(由申请人提供)：糖尿病是一种日益流行的疾病，2型糖尿病患者数量的增加突显了对新的、机械上独特的治疗方法的需求。在这一应用中，将探索胰岛素降解酶(IDE)抑制剂作为糖尿病药物的潜力。之前的工作导致了6bK的发现，这是一种小分子大环IDE抑制剂。6BK是一种高度选择性的IDE抑制剂，其选择性超过1000倍 相关金属蛋白水解酶。结构研究确定，这种选择性来自于6bK结合到IDE表面的一个独特的位置(称为“IDE选择性口袋”)。虽然已经报道了其他IDE抑制剂，但6bK是唯一在体内有效的IDE抑制剂。在6bK中，测试了IDE抑制对糖尿病小鼠模型(HFD喂养的小鼠)的生理影响，与赋形剂处理的小鼠相比，6bK处理的小鼠具有更高的胰岛素水平和更好的口服葡萄糖耐量。此外，这些实验还表明，胰腺激素胰淀素和胰升糖素也是内源性IDE底物。普拉林肽是一种胰淀素类似物和胰淀素受体激动剂，是FDA批准的一种药物，可以减缓胃排空以控制餐后血糖水平。这一信息被用来证明6bK通过提高内源性胰淀素水平来减缓胃排空，提供了6bK用来降低血糖水平的第二个信号通路。IDE抑制剂值得进一步研究，因为它们代表了一种机制上截然不同的潜在糖尿病 药物；唯一能通过损害这些激素的降解来提高胰岛素和胰淀素水平的化合物。药物化学、结构生物学和生理学将被用来确定IDE抑制剂的临床潜力。首先，将使用6bK来确定慢性IDE抑制是否是一种安全有效的糖尿病动物模型治疗方法(目标1)。接下来，将产生并测试利用结构-活性-关系、结构生物学和计算设计的新型IDE抑制剂(目标2)。最后，IDE抑制剂将与批准的糖尿病药物结合使用，以确定降低血糖水平的协同效应(目标3)。这些实验可能会揭示化合物的组合，包括IDE药物，这将是临床上最有用的。总而言之，这些研究应该提供 最清晰的IDE抑制剂临床潜力的图景，并揭示可作为药物开发有用的先导化合物的化合物。

 DESCRIPTION (provided by applicant): Diabetes is a growing epidemic, and the increasing number of type 2 diabetics highlights the need for novel, mechanistically distinct, therapeutics. In this application, the potential of insulin-degrading enzyme (IDE) inhibitors as diabetes drugs will be explored. Preceding work led to the discovery of 6bK, a small-molecule macrocycle IDE inhibitor. 6bK is a remarkably selective IDE inhibitor with greater than 1000-fold selectivity over related metalloproteases. Structural studies determined that this selectivity comes from 6bK binding to a unique site on the IDE surface (referred to as the "IDE-selectivity pocket"). Though other IDE inhibitors have been reported, 6bK is the only IDE inhibitor that is active in vivo. Usin 6bK, the physiological impact of IDE inhibition in mouse models of diabetes (HFD-fed mice) was tested and 6bK-treated mice had higher insulin levels and improved oral glucose tolerance compared to vehicle-treated animals. Furthermore, these experiments revealed that the pancreatic hormones amylin and glucagon are also endogenous IDE substrates. Pramlintide, an amylin analog and amylin receptor agonist, is an FDA-approved drug that slows gastric emptying to control postprandial blood glucose levels. This information was used to demonstrate that 6bK slows gastric emptying by raising endogenous amylin levels, providing a second signaling pathway that 6bK uses to lower blood glucose levels. IDE inhibitors are worth further investigation because they represent a mechanistically distinct class of potential diabetes drugs; the only compounds that raise insulin and amylin levels by impairing the degradation of these hormones. Medicinal chemistry, structural biology, and physiology will be used to determine the clinical potential of IDE inhibitors. First, 6bK will be used to determine whether chronic IDE inhibition is a safe and effective treatment of diabetes in animal models (Aim 1). Next, novel IDE inhibitors that were designed using structure-activity-relationships, structural biology, and computation will be generated and tested (Aim 2). Finally, IDE inhibitors will be used in combination with approved diabetic drugs to identify synergistic effects on lowering blood glucose levels (Aim 3). These experiments might reveal combinations of compounds, including IDE drugs, that will be most useful clinically. Together these studies should provide the clearest picture of the clinical potential of IDE inhibitors, and reveal compounds that can serve as useful lead compounds for drug development.