Novel Small Molecules for Treating Kidney Disease

治疗肾脏疾病的新型小分子

• 批准号: 8057946
• 负责人: DEB K BARMA
• 金额: $ 10万
• 依托单位: CRO LABORATORIES, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8057946
• 关键词: 2,4-thiazolidinedione; ADME Study; Acids; Address; Aging; Albumins; Albuminuria; Alkenes; Amides; Animal Model; Arachidonic Acids; Area; Biological Assay; Biological Preservation; Blood Proteins; Carbon; Carboxylic Acids; Cardiovascular Diseases; Cardiovascular system; Chronic; Chronic Kidney Failure; Creatinine; Cytochrome P450; Data; Development; Diabetes Mellitus; Disease; Dose; Drug Kinetics; Early treatment; Elderly; End stage renal failure; Epoxy Compounds; Ethers; Excretory function; Family; Fibrosis; Filtration; Focal Segmental Glomerulosclerosis; Functional disorder; Goals; Health; Heart Diseases; Hypertension; In Vitro; Incidence; Inhibitory Concentration 50; Injury; Investigational New Drug Application; Kidney; Kidney Diseases; Laboratories; Lead; Medicine; Metabolic; Metabolism; Methods; Modeling; Modern Medicine; Molecular Weight; Morbidity - disease rate; NMR Spectroscopy; Obesity; Outcome; Oxygen; Pathway interactions; Patients; Permeability; Phase; Physiological; Plasma; Proteins; Proteinuria; Public Health; Radiation; Rattus; Recurrence; Regimen; Renal function; Renal glomerular disease; Research Personnel; Role; Serum; Site; Small Business Innovation Research Grant; Staging; Sulfonamides; Sulfur; Surrogate Markers; Symptoms; Techniques; Testing; Therapeutic; Therapeutic Agents; Thiazolidinediones; Thiourea; Time; Toxic effect; Toxicity Tests; Transplantation; Urea; Urine; Vertebral column; Work; absorption; analog; base; chemical stability; cost effective; effective therapy; experience; global health; glomerular filtration; glomerular function; glomerulosclerosis; human disease; human subject; improved; in vitro Assay; in vivo; inorganic phosphate; interstitial; mortality; novel; novel strategies; novel therapeutics; pi bond; prevent; protective effect; response; scaffold; skills; small molecule; therapeutic target; urinary; water solubility

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.

慢性肾脏病（CKD）是一种严重且迅速增长的全球健康危机。CKD与心血管疾病、高血压、糖尿病、肥胖和衰老有关。其特征是肾功能逐渐丧失，蛋白尿（白蛋白尿）、间质纤维化和肾小球硬化增加。尿蛋白的少量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。我们已经使用了体外方法来研究肾小球功能，并已表明，肾小球蛋白屏障受损之前，在几种人类疾病的动物模型的明显蛋白尿的发作。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症（FSGS）。我们已经证明，FSGS患者的血清或血浆中存在的一种因子增加了肾小球白蛋白的体外渗透性（Palb），并导致大鼠蛋白尿。在拟议的研究中，我们将使用由该因素引起的肾小球损伤作为测试潜在治疗剂的模型。我们已经表明，i）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，和ii）8，9-EET和含有两个双键的合成类似物（8，9-EED）保护肾小球滤过屏障免受FSGS渗透因子的影响。8，9-EET的合成类似物是用于开发新的治疗分子以保持正常肾小球滤过屏障功能和管理/治疗与CKD的其他原因相关的肾小球功能障碍的非常有前途的候选物。在该项目的第一阶段，我们计划解决以下具体目标：1。制备五种含有环氧化物生物电子等排体的合成8，9-EED类似物。2.使用体外肾小球白蛋白渗透性试验评价这些合成类似物的肾小球保护作用。我们将使用成熟的技术和专业的技术技能，以获得高纯度和稳定性的合成类似物。将使用体外试验测试和比较类似物对肾小球滤过屏障的保护作用。这些化合物将在我们SBIR项目的第二阶段用作先导化合物，并最终导致提交IND申请，在患有蛋白尿的人类受试者中进行评估。 公共卫生相关性：e尿中蛋白水平升高是许多患者慢性肾病的早期症状，是肾脏中阻止血蛋白进入尿液的过滤器（肾小球）受损的结果。CKD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。我们的工作已经确定了一类新的化合物，这是第一次，将有助于预防和治疗蛋白尿，因此，避免或改善慢性肾脏疾病的进展。