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

 描述（由申请人提供）：糖尿病是一种日益增长的流行病，2型糖尿病患者数量的增加突出了对新的、机制上不同的治疗方法的需求。在本申请中，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6 bK的发现，一种小分子大环IDE抑制剂。6 bK是一种非常有选择性的IDE抑制剂，其选择性超过1000倍。 相关金属蛋白酶。结构研究确定，这种选择性来自6 bK结合到IDE表面上的独特位点（称为“IDE选择性口袋”）。虽然已经报道了其他IDE抑制剂，但6 bK是唯一在体内有活性的IDE抑制剂。使用6 bK，测试了IDE抑制在糖尿病小鼠模型（HFD喂养的小鼠）中的生理影响，并且与媒介物处理的动物相比，6 bK处理的小鼠具有更高的胰岛素水平和改善的口服葡萄糖耐量。此外，这些实验表明，胰腺激素胰淀素和胰高血糖素也是内源性IDE底物。普兰林肽是一种胰淀素类似物和胰淀素受体激动剂，是FDA批准的减缓胃排空以控制餐后血糖水平的药物。该信息用于证明6 bK通过提高内源性胰淀素水平来减缓胃排空，提供6 bK用于降低血糖水平的第二信号传导途径。IDE抑制剂值得进一步研究，因为它们代表了一类潜在糖尿病的机制 药物;唯一通过削弱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用于确定IDE抑制剂的临床潜力。首先，6 bK将用于确定慢性IDE抑制是否是动物模型中糖尿病的安全有效治疗（目的1）。接下来，将生成并测试使用结构-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抑制剂将与获批的糖尿病药物联合使用，以确定对降低血糖水平的协同作用（目的3）。这些实验可能会揭示化合物的组合，包括IDE药物，这将是最有用的临床。这些研究应提供 这是IDE抑制剂临床潜力的最清晰的图片，并揭示了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.