Novel and Kidney Selective AMPK Activators to Treat Polycystic Kidney Disease

治疗多囊肾病的新型肾脏选择性 AMPK 激活剂

基本信息

批准号：
8905787
负责人：
Ken W Batchelor
金额：
$ 47.43万
依托单位：
NOVATARG, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-16 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8905787
关键词：
Achievement Affect Animal Model Anions Autosomal Dominant Polycystic Kidney Biguanides Bilateral Biological Assay Biological Availability Canis familiaris Cell Culture Techniques Cell Line Cell Proliferation Cells Chronic Kidney Failure Cleaved cell Clinical Clinical Trials Collaborations Collagen Complication Consumption Cyclic AMP Cyst Cystic Fibrosis Transmembrane Conductance Regulator Cystic kidney Development Disease Drug Formulations Drug Kinetics Embryo End stage renal failure Epithelial Cells FDA approved Flank Pain Fluids and Secretions Folic Acid Growth Human Hypertension In Vitro Inherited Inhibitory Concentration 50 Institutes Kansas Kidney Kidney Diseases Kidney Transplantation Lactic Acidosis Lead Life Liquid substance Liver Maximum Tolerated Dose Mediating Medical Economics Medical center Metformin Mus Mutant Strains Mice Nephrons No-Observed-Adverse-Effect Level Organ Culture Techniques Organic Cation Transporter POU2F1 gene Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Phase Polycystic Kidney Diseases Preparation Prevalence Prodrugs Property Rattus Relative (related person)Renal clearance function Renal dialysis Renal function Reporting Research Research Personnel Risk Safety Signal Transduction Sirolimus Small Business Innovation Research Grant Staging Structure Structure-Activity Relationship System Testing Universities V2 Receptors Vasopressins Work analog base cost drug candidate drug discovery drug testing economic cost folate-binding protein human FRAP1 protein in vivo Model innovation kidney cell liver injury mTOR Inhibitor mTOR Signaling Pathway mTOR inhibition mutant mouse model novel novel therapeutic intervention patient population preclinical study prevent programs public health relevance receptor mediated endocytosis screening tolvaptan uptake

项目摘要

DESCRIPTION (provided by applicant): Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the presence of innumerous fluid filled cysts that progressively enlarge, leading nephron loss and the progressive decline in renal function. Aberrant proliferation of the cyst-lining epithelial cells and the accumulation of fluid within the cysts du to Cl-dependent fluid secretion are responsible for the growth of the cysts. During the past fifteen years, there has been enormous amounts information gained from PKD research; however there is still a lack of understanding on how to effectively treat the disease. Tolvaptan, a vasopressin V2 receptor antagonist, was highly effective in animals models of PKD and significantly slow PKD progression in patients of the TEMPO trial; however, the drug caused liver complications is some patients and was not approved by the FDA for treatment of PKD. mTOR inhibitors, such as rapamycin, are also being considered as potential disease modifying therapies, however, clinical trials of these agents have been disappointing. One concern is that circulating concentrations of the drug at concentrations that are tolerated relatively well may not be sufficient to inhibit mTOR in the kidneys. Recently, folate-conjugated rapamycin was shown to specifically target the kidney since the pro drug was taken up by the folate receptor-mediated endocytosis and cleaved releasing the active rapamycin within the kidney cells. NovaTarg, in collaboration with the Kidney Institute at the University of Kansas Medical Center, has identified an innovative approach to inhibit cyst growth. Taking advantage of the focused medicinal chemistry program at NovaTarg and the expertise of the PKD investigators at KUMC, we have developed kidney-specific AMPK activators that inhibit ADPKD cell proliferation through p53 and the mTOR pathway, and fluid secretion driven by CFTR mediated Cl- secretion. Our approach is based on the synthesis of novel biguanides, analogues of metformin that utilize the kidney specific organic cation transporter 2 (OCT2) to enter kidney cells and to activate AMPK in the cyst-lining cells. Biguanides are very basic compounds which require OCTs for cellular entry, but metformin itself does not discriminate between OCT1 (liver) and OCT2 (kidney). An important complication of the use of metformin in patients with chronic kidney disease is the development of lactic acidosis due to the accumulation of the drug in the liver. Thus NovaTarg has synthesized >130 biguanide analogues of metformin to identify biguanides that are selectively transported by OCT2 to target kidney cells. An early lead compound, NT1021 activated AMPK in human ADPKD cells, leading to inhibition of mTOR- mediated cell proliferation and transepithelial Cl secretion. In addition, NT1021 blocked in vitro cyst formation of ADPKD cells cultured within a collagen matrix and the expansion of cyst-like structures in Pkd-/- mouse embryo kidneys ex vivo. We think that highly OCT2 selective biguanides will avoid liver uptake by OCT1 and display the safety profile required for this population of patients. During Phase 1 of the SBIR, NovaTarg discovered a highly OCT2-selective biguanide NT1096 that has higher selectivity for OCT2 than NT1021, but is not quite as potent. In Phase 2, we will synthesis derivatives of NT1096 for hit-to-lead optimization and evaluate the drug in preclinical studies and prepare for testing the drug is a proof-of-principal clinical trial.

描述（由应用程序提供）：常染色体显性多囊肾脏疾病（ADPKD）的特征是存在无数液体填充囊肿，这些囊肿逐渐扩大，领先的肾单位丧失和肾功能的逐渐下降。囊肿上皮细胞的异常增殖以及在囊肿到CL依赖性液体中的流体积累是囊肿的生长。在过去的十五年中，从PKD研究中获得了大量信息。但是，仍然缺乏对如何有效治疗疾病的了解。 Tolvaptan是一种加压素V2受体拮抗剂，在PKD的动物模型中非常有效，并且Tempo试验患者的PKD进展显着慢。但是，引起肝脏并发症的药物是某些患者，未经FDA批准用于治疗PKD。 MTOR抑制剂（例如雷帕霉素）也被认为是改变疗法的潜在疾病，但是，这些药物的临床试验令人失望。一个问题是，在相对良好的浓度下，药物的循环浓度可能不会足以抑制儿童中的mtor。最近，由于叶酸受体介导的内吞作用，并清除了肾细胞中的活性雷帕霉素，因此显示出叶酸偶联的雷帕霉素特异性靶向肾脏。 Novatarg与堪萨斯大学医学中心的肾脏研究所合作，确定了一种抑制囊肿增长的创新方法。利用Novatarg的重点医学化学计划以及KUMC的PKD研究人员的专业知识，我们开发了肾脏特异性AMPK激活剂，这些AMPK激活剂通过p53和MTOR途径抑制ADPKD细胞增殖，以及由CFTR介导的CL- CL-分泌驱动的流体分泌。我们的方法基于使用肾脏特异性有机阳离子转运蛋白2（OCT2）的二甲双胍的新型Biguanides的合成，以进入肾细胞并激活囊肿细胞中的AMPK。 Biguanides是非常基本的化合物，需要OCT进行细胞进入，但是二甲双胍本身并不能区分OCT1（肝脏）和OCT2（肾脏）。二甲双胍在慢性肾脏疾病患者中使用的重要并发症是由于药物在肝脏中积累而导致乳酸性酸中毒的发展。 Novatarg合成了> 130个二甲双胍的Biguanide类似物，以鉴定由Oct2选择性运输的Biguanides，以靶向肾细胞。早期的铅化合物NT1021在人ADPKD细胞中激活了AMPK，从而抑制了MTOR介导的细胞增殖和跨性别CL分泌。另外，NT1021阻塞了体外囊肿在胶原蛋白基质中培养的ADPKD细胞以及pKD - / - 小鼠胚胎肾脏中的囊肿样结构的扩展。我们认为，高度OCT2选择性BIGUANIDE将避免在OCT1到OCT1的肝脏摄取，并显示该患者人群所需的安全性。在SBIR的第1阶段，Novatarg发现了高度OCT2选择性的Biguanide NT1096，其对OCT2的选择性高于NT1021，但并没有那么潜力。在第2阶段，我们将合成NT1096的衍生物进行命中率优化，并在临床前研究中评估该药物，并准备测试该药物是一项主要临床证明。