Novel Small Molecules for Treating Kidney Disease

描述：慢性肾脏疾病(CKD)是一种严重且迅速增长的全球健康危机。慢性肾脏病与心血管疾病、高血压、糖尿病、肥胖和衰老有关。它的特征是肾功能逐渐丧失，蛋白尿(蛋白尿)增加，间质纤维化和肾小球硬化。尿蛋白的轻微增加与发病率和死亡率的显著增加有关。因此，蛋白尿是现代医学的重要治疗靶点。我们使用体外方法研究肾小球功能，并表明在几种人类疾病的动物模型中，在出现显性蛋白尿之前，肾小球蛋白屏障受损。这些模型包括高血压、糖尿病和原发性肾小球疾病局灶性节段性肾小球硬化(FSGS)。我们已经证明，FSGS患者血清或血浆中存在的一种因子增加了体外肾小球白蛋白通透性(PALB)，并导致大鼠蛋白尿。在拟议的研究中，我们将使用该因素引起的肾小球损伤作为测试潜在治疗药物的模型。我们发现，1)8，9-环氧二十碳三烯酸(8，9-EET)是维持肾小球滤过屏障完整性所必需的物质，而2)8，9-EET和含有两个双键的合成类似物(8，9-EED)可以保护肾小球滤过屏障免受FSGS通透性因子的影响。8，9-EET的合成类似物是非常有希望开发新的治疗分子以保护正常的肾小球滤过屏障功能和管理/治疗与其他原因的CKD相关的肾小球功能障碍的候选药物。在这个项目的第一阶段，我们计划解决以下具体目标：1.合成5个含有环氧化物生物等位体的8，9-EED类似物。2.用体外肾小球白蛋白通透性实验评价这些合成类似物对肾小球的保护作用。我们将利用成熟的技术和专业的技术技能来获得高纯度和稳定性的合成类似物。类似物将通过体外实验测试和比较它们对肾小球滤过屏障的保护作用。这些化合物将被用作我们SBIR项目第二阶段的先导化合物，并最终将提交IND申请，以评估患有蛋白尿的人类受试者。 公共卫生相关性：在大量患者中，尿蛋白水平升高是慢性肾脏疾病(CKD)的早期症状，是肾脏中阻止血液蛋白进入尿液的滤器(肾小球)受损的结果。慢性肾脏病是一个主要的健康问题，特别是在老年人和糖尿病或心脏病患者中。我们的工作首次确定了一类新的化合物，它们将有助于预防和治疗蛋白尿，从而避免或改善慢性肾脏疾病的进展。

DESCRIPTION: Chronic kidney disease (CKD) is a significant and rapidly growing global health crisis. CKD is associated with cardiovascular disease, hypertension, diabetes, obesity, and aging. It is characterized by gradual loss of renal function with increasing proteinuria (albuminuria), interstitial fibrosis, and glomerulosclerosis. Small increases in urinary protein are associated with markedly increased morbidity and mortality. Thus, proteinuria is an important therapeutic target in modern medicine. We have used an in vitro method to study glomerular function and have shown that the glomerular protein barrier is impaired prior to the onset of overt proteinuria in animal models of several human diseases. These models include hypertension, diabetes mellitus, and the primary glomerular disease, focal segmental glomerulosclerosis (FSGS). We have shown that a factor present in serum or plasma of patients with FSGS increases glomerular albumin permeability in vitro (Palb) and causes proteinuria in rats. In the proposed studies, we will use the glomerular injury caused by this factor as a model for testing potential therapeutic agents. We have shown that, i) 8,9-epoxyeicosatrienoic acid (8,9-EET) is required to maintain the integrity of the glomerular filtration barrier and, ii) 8,9-EET and synthetic analogs containing two double bonds (8,9-EEDs) protect the glomerular filtration barrier from the effects of FSGS permeability factor. The synthetic analogs of 8,9-EET are highly promising candidates for developing new therapeutic molecules to preserve normal glomerular filtration barrier function and to manage/treat glomerular dysfunction associated with other causes of CKD. During Phase-1 of this project, we plan to address the following Specific Aims: 1. Prepare five synthetic 8,9-EED analogs containing epoxide bioisosteres. 2. Evaluate glomerular protection of these synthetic analogs using an in vitro glomerular albumin permeability assay. We will use established techniques and expert technical skills to obtain synthetic analogs of high purity and stability. Analogs will be tested and compared for their protective effect on the glomerular filtration barrier using the in vitro assay. These compounds will be used as lead compounds during the Phase-II of our SBIR project, and will ultimately lead to file an IND application evaluating in human subjects with proteinuria. PUBLIC HEALTH RELEVANCE: e Increased protein level in the urine is an early symptom of chronic kidney disease (CKD) in a large number of patients and is a consequence of damage to the filters (glomeruli) in the kidney that prevent blood proteins from passing into urine. CKD is a major health problem, especially among the elderly and those with diabetes or heart disease. Our work has identified a new class of compounds that, for the first time, will be useful in preventing and treating proteinuria and, therefore, avoiding or ameliorating the progression of chronic kidney disease.