NOVEL AGENTS TO PREVENT KIDNEY DISEASE IN DIABETES

描述（改编自应用程序）：项目的目标 是合成和开发一种小分子， 糖基化性质，并且适合于治疗用途， 糖尿病肾病第一阶段的主要目标是合成类似物 的杂芳基乙酸类化合物，并测试它们的 抑制白蛋白非酶糖化的能力。的理由 因为这项工作来源于调查人员最近的研究， 糖化白蛋白诱导胶原蛋白、纤连蛋白和 肾小球系膜细胞中的TGF-β;单克隆抗体的施用 抗修饰白蛋白抗体降低尿蛋白升高 排泄，抑制系膜基质积聚，并防止过度- 分子成分的表达;这些影响与 尽管事实上， 高血糖持续存在;一种名为EX 0 -226的小分子抑制了高血糖。 在体外和体内形成糖化白蛋白;和显著的 尿蛋白排泄的减少伴随着血浆中 糖化白蛋白在第一阶段，研究人员将综合和 系统地测试这种化合物的类似物， 保留和优化抗糖化特性，并最大限度地减少或消除 环加氧酶抑制活性与不希望的 副作用. 拟定商业应用： 未提供拟议的商业应用。

DESCRIPTION (Adapted from the application): The objective of the project is to synthesize and develop a small molecule that possesses anti- glycation properties and that is appropriate for therapeutic use in diabetic nephropathy. The major goal in Phase I is to synthesize analogs of a compound in the heteroaryl acetic acid class and to test their ability to inhibit the non-enzymatic glycation of albumin. The rationale for the work derives the investigators recent studies that demonstrated that glycated albumin induces expression of collagen, fibronectin, and TGF-beta in renal glomerular mesangial cells; administration of monoclonal antibodies against modified albumin reduce elevated urinary protein excretion, inhibits mesangial matrix accumulation, and prevents the over- expression of the molecular components; these effects are associated with a reduction of elevated plasma glycated albumin despite the fact that hyperglycemia persists; a small molecule designated EX0-226, inhibits the formation of glycated albumin in vitro and in vivo; and a significant reduction in urine protein excretion accompanies the decrease in plasma glycated albumin. In Phase I the investigator will synthesize and systematically test analogs of this compound that have been designed to retain and optimize anti-glycated properties, and minimize or eliminate cyclooxygenase inhibitory activities which are associated with undesirable side effects. PROPOSED COMMERCIAL APPLICATION: Proposed commercial application not available.