Selectin inhibitor therapeutics for blood flow related complications of diabetes

描述（由申请人提供）：拟议研究的最终目标是开发用于糖尿病血流相关并发症的拟糖疗法。特别地，本文提出的研究旨在优化我们的E-选择素的专有有效抑制剂的功效和口服生物利用度，目的是干扰血管内皮选择素和白细胞表面上表达的碳水化合物之间的相互作用。我们假设这些糖模拟物化合物可以被开发为具有预防或延迟糖尿病的血流相关并发症如肾病和视网膜病的发作的预期结果的先导治疗剂。肥胖和糖尿病是目前美国和世界范围内的主要问题，预计在不久的将来，它们的发生率将急剧上升。糖尿病的主要问题之一是微血管系统中的血液流动不良，这导致许多心血管并发症。许多研究将可溶性血浆粘附分子E-选择素描述为肥胖和糖尿病的标志物，表明称为内皮功能障碍的慢性低度炎症状况。作为粘附分子，E-选择素表达导致血管内细胞滚动和束缚增加，从而限制血流，特别是微血管内的血流。可溶性E-选择素的水平与血流减少引起的并发症相关，如糖尿病肾病和视网膜病变。我们已经合理地设计了一个家庭的小分子糖模拟物的化合物，是有效的拮抗剂E-选择素。我们的初步结果表明，这些糖模拟E-选择素抑制剂防止细胞粘附，从而增加糖尿病小鼠的血流量。在本文提出的研究中，我们的努力将致力于优化具有增加的活性和口服生物利用度的先导化合物。我们将首先使用E-选择素基因敲除小鼠来验证E-选择素在糖尿病视网膜病变和肾病中的作用（具体目标1.1）。然后，我们将使用链脲佐菌素诱导的糖尿病小鼠来测试我们的拟糖E-选择素抑制剂在抑制白细胞停滞和增加视网膜毛细血管中的血流量（具体目标1.2）以及预防肾病（具体目标1.3）方面的效力。然后根据Lipinski的5法则以及吸收、分布、代谢和排泄（ADME）研究（具体目标2），选择具体目标1中选择的化合物进行口服生物利用度研究。在完成这项拟议的研究时，我们预计已经选择了一种先导糖模拟E-选择素抑制剂，然后将其进一步优化为糖尿病血流并发症的潜在治疗药物。公共卫生相关性：肥胖和糖尿病在美国和世界范围内日益流行，并与多种心血管并发症相关。拟议研究的最终目标是测试我们的几种化合物-合理设计以模拟存在于血细胞表面的碳水化合物-它们阻断炎症最初步骤之一的能力，从而减轻一些与糖尿病相关的血流并发症。

DESCRIPTION (provided by applicant): The ultimate objective of the proposed research is to develop glycomimetic therapeutics for blood flow related complications of diabetes. In particular, the research proposed herein aims to optimize our proprietary potent inhibitors of E-selectin for both efficacy and oral bioavailability, with the intention of interfering with the interaction between vascular endothelial selectins and carbohydrates expressed on the surface of leukocytes. We hypothesize that these glycomimetic compounds can be developed as lead therapeutics with the intended consequence of preventing or delaying the onset of blood flow related complications of diabetes such as nephropathy and retinopathy. Obesity and diabetes are currently major problems in the U.S. and worldwide, and their occurrence is projected to rise sharply in the near future. One of the major problems in diabetes is poor blood flow in the microvasculature, which leads to a host of cardiovascular complications. Numerous studies describe the soluble plasma adhesion molecule, E-selectin, as a marker for obesity and diabetes, indicating a chronic low grade inflammatory condition known as endothelial dysfunction. As an adhesion molecule, E-selectin expression results in increased cell rolling and tethering within the blood vessels, thereby restricting blood flow, particularly within the microvasculature. Levels of soluble E-selectin correlate with complications due to reduced blood flow such as diabetic nephropathy and retinopathy. We have rationally designed a family of small molecule glycomimetic compounds that are potent antagonists of E-selectin. Our preliminary results demonstrate that these glycomimetic E-selectin inhibitors prevent cell adhesion and thus increase blood flow in diabetic mice. In the research proposed herein, our effort will be devoted to optimizing a lead compound with increased activity and oral bioavailability. We will first use E-selectin knockout mice to validate the role that E-selectin plays in diabetic retinopathy and nephropathy (Specific Aim 1.1). Then, we will use streptozotocin-induced diabetic mice to test our glycomimetic E-selectin inhibitors for their potency in inhibiting leukostasis and increasing blood flow in retinal capillaries (Specific Aim 1.2), and preventing nephropathy (Specific Aim 1.3). Compounds selected in Specific Aim 1 will then be selected for oral bioavailability, based on Lipinski's Rule of 5 as well as Absorption, Distribution, Metabolism and Excretion (ADME) studies (Specific Aim 2). At the completion of this proposed study we expect have selected a lead glycomimetic E-selecin inhibitor which will then be further optimizing as a potential therapeutic for blood flow complications of diabetes. PUBLIC HEALTH RELEVANCE: Obesity and diabetes are a growing epidemic in the U.S. and worldwide, and are associated with a multitude of cardiovascular complications. The ultimate objective of the proposed research is to test several of our compounds - rationally designed to mimic carbohydrates present on the surface of blood cells - for their ability to block one of the initial steps of inflammation, thereby mitigating some of the blood flow related complications of diabetes.