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.
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.
