DIABETIC RETINOPATHY--THERAPY WITH GLYCATION INHIBITORS

这项提案的总体目标是开发一种可口服的 防治糖尿病视网膜病变的小分子药物 --美国成年人新增失明的主要原因。在.期间 在这项提案的第一阶段，我们证明了 抗糖基化药物EXO-226对糖尿病啮齿动物模型的降糖作用 糖化白蛋白在血浆中的浓度，并防止 糖尿病视网膜病变的形态异常特征及临床意义 肾病。在第二阶段，EXO-226给药的研究 将推广到糖尿病啮齿动物，以提供进一步的概念证明 降低血浆糖化白蛋白对预防高血压病有一定作用 或逆转糖尿病视网膜病变。EXO-226的结构类似物 将被合成以产生其中抗糖基化的化合物 活性最大化，环氧合酶活性最小化(至 防止胃肠道刺激)。领先的候选人将类比 研究其在啮齿动物体内的吸收、生物分布和毒理学。 在这些研究的基础上，将给出适当剂量的类似物 以确定它们的抗糖化活性，并为 它们阻止或逆转形态变化的能力 在这些模型中糖尿病视网膜病变的特点。最后， Exo-226将在6个月内用于糖尿病患者 确定抗糖化治疗是否会减少 代表视网膜血管系统的物质的渗漏 糖尿病视网膜病变最早的功能性视网膜异常。 建议的商业应用 该项目中描述的研究和开发预计将 导致用于预防/治疗糖尿病的新的化学物质 视网膜病变。

The overall objective of this proposal is to develop an orally available small molecule for the prevention and treatment of diabetic retinopathy - the leading cause of new blindness among adults in America. During Phase I of this proposal, we demonstrated that the administration of the anti-glycation agent, EXO-226, to rodent models of diabetes lowered the concentration of glycated albumin in the plasma and prevented the morphological abnormalities characteristic of diabetic retinopathy and nephropathy. During Phase II, those studies of EXO-226 administration to diabetic rodents will be extended to provide further proof of concept that lowering of plasma glycated albumin is effective in the prevention or reversal of diabetic retinal disease. Structural analogs of EXO-226 will be synthesized to produce compounds in which anti-glycation activity is maximized and cyclo-oxygenase activity is minimized (to prevent gastrointestinal irritation). The lead candidate analogs will be studied for absorption, biodistribution and toxicology in rodents. Based on those studies, appropriate doses of the analogs will be given to diabetic rodents to determine their anti-glycation activity and for their ability to prevent or reverse the morphological changes characteristic of diabetic retinopathy in these models. Finally, EXO-226 will be administered to diabetic human subjects over a 6 months period to determine whether anti-glycation therapy will reduce the leakage of substances from the retinal vasculature that represents the earliest functional retinal abnormality of diabetic retinopathy. PROPOSED COMMERCIAL APPLICATION The research and development described in this project is expected to lead to new chemical entities for the prevention/treatment of diabetic retinopathy.