Alpha Lipoic Acid Derivatives for Treatment of Hypertension

描述（由申请人提供）：α硫辛酸（ALA）是一种天然存在的八碳脂肪酸，由植物和动物（包括人类）合成，具有有效的抗氧化、抗炎和线粒体保护特性。ALA诱导体重减轻，降低胆固醇，增加葡萄糖摄取，减少炎症分子的表达，改善血管功能。我们建议通过开发一类从ALA衍生的新型治疗分子来挖掘ALA衍生物在降压治疗中的潜力。我们对原型化合物INV 65-05的初步体内和体外研究令人鼓舞，并为该方法的优点提供了希望。因此，我们计划进行基于ALA的治疗方法的合成和表征，并在一年内提出三个具体目标。在Specific Aim 1a中，我们计划使用模拟研究来优化结构，我们将合成和表征天然可用的ALA衍生的小分子。在特定的目标1b中，我们将测试ACE抑制功能，并通过体外抗氧化作用和内皮保护来确定选定化合物的功效。在具体目标2a-c中，我们将使用实验动物模型（自发性高血压大鼠卒中易发模型）研究目标1中鉴定的2种精选多功能化合物降低高血压的体内功效。我们将评估这些药物在减少血管炎症、内皮保护、心肺ACE活性、主动脉超氧化物生成等方面的具体作用。在具体的aim 3中，我们将进一步将aim 1衍生的铅分子修饰为“一氧化氮”释放药物，并提出测试其在NO释放方面的功效以及体外检测。这一科学建议的成功完成将导致创造一类具有独特治疗效果的新型分子。将确定一个主要候选药物，并通过II期资助进一步测试药代动力学、安全性和毒性。这将导致向FDA提交IND，以执行I/II期临床试验。

DESCRIPTION (provided by applicant): Alpha lipoic acid (ALA) is a naturally occurring eight-carbon fatty acid that is synthesized by plants and animals, including humans and possesses potent antioxidant, anti-inflammatory and mitochondrial protectant properties. ALA induces weight loss, lowers cholesterol, increases glucose uptake, decreases the expression of inflammatory molecules and improves vascular function. We propose to tap the potentials of ALA derivatives for antihypertensive therapies by developing a novel class of therapeutic molecules derived from ALA. Our preliminary in-vivo and in-vitro studies with the prototype compound, INV 65-05 have been encouraging and provide promise that this approach has merit. Accordingly, we plan to undertake the synthesis and characterizations of ALA based therapeutics and propose three specific aims over one year period. In Specific Aim 1a, we plan to optimize the structures using simulation studies and we will synthesize and characterize small molecules derived from naturally available ALA. In specific aim 1b, we will test ACE inhibitory functionality and establish their efficacy of select compounds using in-vitro assays for antioxidant effects, endothelial protection. In specific aims 2a-c, we will study the in-vivo efficacy of 2 select multifunctional compounds identified in Aim 1 in lowering hypertension using experimental animal models (spontaneously hypertensive rat stroke prone model). We will evaluate the specific effects of these agents in reducing vascular inflammation, endothelial protection, ACE activity in heart and lung, super oxide generation in the aorta. In specific aim 3, we will further modify lead molecules derived from Aim 1 into "nitric oxide" releasing drugs and propose testing their efficacy with regards to NO release as well as the in-vitro assays. Successful completion of this scientific proposal will result in the creation of a novel class of molecules with unique therapeutic effects. A lead candidate will be identified and further tested through a Phase II grant for pharmacokinetics, safety and toxicity. This will then lead to an IND submission to the FDA for execution of Phase I/II clinical trials. PUBLIC HEALTH RELEVANCE: Hypertension affects millions of adult Americans and is a major risk factor for myocardial infarction, stroke, heart failure, and renal failure. . Alpha lipoic acid (ALA) is a naturally occurring eight-carbon fatty acid that is synthesized by plants and animals, including humans and possesses potent antioxidant, anti-inflammatory and mitochondrial protectant properties. ALA induces weight loss, lowers cholesterol, increase glucose uptake, increases glutathione, decreases the expression of inflammatory molecules and improves vascular function. The objective of this proposal is to design, synthesize, and characterize a new class of bio-compatible molecules possessing multi- functional therapeutics and ideal pharmacokinetic properties based on specific modifications of ALA. The proposed derivatives would have ACE inhibitory properties, lowering blood pressure, antioxidant effects and "nitric oxide" releasing functionality and further study their effects with in vitro and in vivo models. The outcomes of this study will help to further advance the commercial development of such molecules.