Selectin inhibitor therapeutics for blood flow related complications of diabetes

选择素抑制剂治疗糖尿病血流相关并发症

• 批准号: 7866456
• 负责人: John L. Magnani
• 金额: $ 15.96万
• 依托单位: GLYCOMIMETICS, INC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7866456
• 关键词: ADME Study; Adhesions; Albumins; Biological Availability; Blood; Blood Cells; Blood Vessels; Blood capillaries; Blood flow; Carbohydrates; Cardiovascular system; Cell Adhesion; Cell Adhesion Molecules; Cells; Chronic; Clinical; Complications of Diabetes Mellitus; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic Retinopathy; Diabetic mouse; Disease; Drug Formulations; E-Selectin; Endothelium; Epidemic; Excretory function; Family; Functional disorder; Future; Genetic; Glucose; Goals; Histology; Hyperglycemia; Inflammation; Inflammatory; Intention; Kidney Diseases; Knockout Mice; Laboratories; Lead; Leukocyte Rolling; Leukocytes; Leukostasis; Measures; Metabolism; Mus; Obesity; Oral; Pharmaceutical Preparations; Plasma; Play; Process; Proteins; Publishing; Qualifying; Reporting; Research; Retina; Retinal; Retinal Diseases; Role; Safety; Selectins; Serum Proteins; Streptozocin; Surface; Testing; Therapeutic; Vascular Endothelial Cell; absorption; base; capillary; design; follow-up; improved; in vivo; inhibitor/antagonist; intravenous injection; intravital microscopy; pre-clinical; prevent; public health relevance; small molecule; subcutaneous; sugar; urinary

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.

描述(申请人提供)：拟议研究的最终目标是开发治疗糖尿病血流相关并发症的拟糖疗法。特别是，本文提出的研究旨在优化我们专利的E-选择素有效抑制剂的有效性和口服生物利用度，目的是干扰血管内皮细胞选择素与白细胞表面表达的碳水化合物之间的相互作用。我们推测，这些类糖化合物可以被开发为铅治疗药物，预期的结果是预防或延迟糖尿病血流相关并发症的发生，如肾病和视网膜病变。肥胖和糖尿病目前是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血流不畅，这会导致一系列心血管并发症。大量研究将可溶性血浆黏附分子E-选择素描述为肥胖和糖尿病的标志，表明这是一种被称为内皮功能障碍的慢性低度炎症状态。作为一种黏附分子，E-选择素的表达导致血管内细胞滚动和拴系增加，从而限制血流，特别是在微血管内。可溶性E-选择素水平与糖尿病肾病和视网膜病变等血流减少引起的并发症相关。我们合理地设计了一类能有效拮抗E-选择素的小分子拟糖化合物。我们的初步结果表明，这些糖类E-选择素抑制剂可以防止细胞黏附，从而增加糖尿病小鼠的血流量。在本文提出的研究中，我们将致力于优化具有更高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所起的作用(特定目标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类血糖E-选择素抑制剂在抑制白血球淤积和增加视网膜毛细血管血流量(特定目标1.2)和预防肾病(特定目标1.3)方面的效力。然后，根据利平斯基规则5以及吸收、分布、代谢和排泄(ADME)研究(特定目标2)，选择特定目标1中选择的化合物进行口服生物利用度。在这项拟议的研究完成后，我们预计已经选择了一种先导型糖化E-选择素抑制剂，然后将进一步优化，作为治疗糖尿病血流并发症的潜在药物。公共卫生相关性：肥胖和糖尿病在美国和世界范围内是一种日益流行的疾病，并与多种心血管并发症有关。这项拟议研究的最终目标是测试我们的几种化合物--经过合理设计以模拟血细胞表面存在的碳水化合物--是否有能力阻止炎症的初始步骤之一，从而减轻糖尿病的一些与血流相关的并发症。