THR-0921 for Cardiovascular Complications of Diabetes

THR-0921 用于糖尿病心血管并发症

• 批准号: 7154903
• 负责人: EDWARD P AMENTO
• 金额: $ 10万
• 依托单位: THERACOS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7154903
• 关键词: antiinflammatory agents; arginine; blood glucose; cardiovascular disorder chemotherapy; cardiovascular disorder prevention; cardiovascular pharmacology; carotid artery; chemoprevention; disease /disorder model; free radical oxygen; glucose tolerance test; insulin sensitivity /resistance; intraluminal angioplasty; laboratory rat; medical complication; nitric oxide synthase; nonhuman therapy evaluation; noninsulin dependent diabetes mellitus; oxidoreductase inhibitor; peroxisome proliferator activated receptor; restenosis

DESCRIPTION (provided by applicant): Project Summary/Abstract: Resistance to insulin-mediated glucose disposal is now recognized as the earliest abnormality in glucose tolerant individuals (nondiabetics) who will eventually develop type 2 diabetes. In addition to being a risk factor for atherosclerosis, recent studies have established that patients with type 2 diabetes also demonstrate increased rate of restenosis after angioplasty. Our preliminary studies indicate that insulin resistance, in the absence of frank hyperglycemia, is associated with enhanced restenosis in a rat model of balloon injury, as well as increased inflammation as determined by vascular production of reactive oxygen species and enhanced expression of inflammatory genes. Moreover, insulin resistance is associated with increased circulating levels of the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine (ADMA), providing another mechanism for the accelerated restenotic response. THR-0921 is a novel insulin sensitizing compound that has potent glucose-lowering activity, modest PPAR-y activity, as well as anti-inflammatory actions. This proposal will test the efficacy of THR-0921 to inhibit restenosis in a rat model of insulin resistance as well as its effects on ADMA levels. Accordingly, we will use our in vivo model to address these specific aims: 1) To expand upon our initial findings to determine the potential therapeutic applicability of THR-0921 in the control of restenosis, particularly in the setting of insulin resistance. 2) To determine the efficacy of THR-0921 to reduce ADMA levels in insulin resistant animals. If the SBIR phase I results show activity in our animal model of insulin resistance, the goal in an SBIR phase II study will be to pursue clinical development of THR-0921 for the treatment of insulin resistance and type 2 diabetes. The goal will be to develop a potent insulin sensitizer with demonstrated effects on cardiovascular biology that has a reduced side effect profile compared with traditional thiazolidinediones. Project Narrative: People who develop diabetes as adults (type 2 diabetes) often have related conditions such as obesity that increase their risk for developing coronary heart disease. Unfortunately, the newest drugs commonly used to treat type 2 diabetes have undesired side effects that further increase the risk of heart disease. The current study is designed to evaluate a new drug in this class that not only appears to have fewer heart-related side effects, but also may help reduce complications that arise from certain surgical procedures used to treat coronary heart disease.

描述（由申请人提供）： 项目摘要/摘要：对胰岛素介导的葡萄糖处理的抵抗现在被认为是最终发展为 2 型糖尿病的葡萄糖耐受个体（非糖尿病患者）中最早的异常。最近的研究表明，2 型糖尿病除了是动脉粥样硬化的危险因素外，血管成形术后再狭窄的发生率也会增加。我们的初步研究表明，在没有明显高血糖的情况下，胰岛素抵抗与球囊损伤大鼠模型中的再狭窄增强以及由血管产生活性氧和炎症基因表达增强所确定的炎症增加有关。此外，胰岛素抵抗与内源性一氧化氮合酶抑制剂、不对称二甲基精氨酸（ADMA）循环水平升高有关，这为加速再狭窄反应提供了另一种机制。 THR-0921 是一种新型胰岛素增敏化合物，具有有效的降血糖活性、适度的 PPAR-y 活性以及抗炎作用。该提案将测试 THR-0921 在胰岛素抵抗大鼠模型中抑制再狭窄的功效及其对 ADMA 水平的影响。因此，我们将使用我们的体内模型来实现这些具体目标：1) 扩展我们的初步发现，以确定 THR-0921 在控制再狭窄方面的潜在治疗适用性，特别是在胰岛素抵抗的情况下。 2) 确定 THR-0921 降低胰岛素抵抗动物 ADMA 水平的功效。如果 SBIR I 期结果显示我们的胰岛素抵抗动物模型具有活性，那么 SBIR II 期研究的目标将是进行 THR-0921 的临床开发，用于治疗胰岛素抵抗和 2 型糖尿病。我们的目标是开发一种有效的胰岛素增敏剂，其对心血管生物学的影响已得到证实，与传统的噻唑烷二酮类药物相比，其副作用减少。项目叙述：成年后患糖尿病（2 型糖尿病）的人通常患有肥胖等相关疾病，这些疾病会增加患冠心病的风险。不幸的是，常用于治疗 2 型糖尿病的最新药物具有不良副作用，进一步增加患心脏病的风险。目前的研究旨在评估此类新药，该药物不仅具有较少的与心脏相关的副作用，而且可能有助于减少用于治疗冠心病的某些外科手术引起的并发症。