Alpha Lipoic Acid Derivatives for Treatment of Hypertension

用于治疗高血压的α-硫辛酸衍生物

基本信息

批准号：
7926606
负责人：
Desikan Rajagopal
金额：
$ 19.07万
依托单位：
INVASC THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7926606
关键词：
Acids Adult Adverse effects Affect American Animals Anti-Inflammatory Agents Anti-inflammatory Antihypertensive Agents Antioxidants Aorta Ascorbic Acid Binding Biological Products Blood Vessels Body Weight decreased Carbon Cardiovascular Diseases Cells Chemicals Cholesterol Chronic Clinical Clinical Trials Computer Assisted Development Disease Dose Drug Combinations Drug Delivery Systems Drug Interactions Drug Kinetics Endothelium Energy Metabolism Enzyme Inhibition Enzymes Experimental Animal Model Fatty Acids Generations Glutathione Grant Heart Heart failure Hepatotoxicity Human Hybrids Hypertension Hypertriglyceridemia Hypotension In Vitro Inbred SHR Rats Inflammatory Kidney Failure Lead Lung Mitochondria Modeling Modification Molecular Models Myocardial Infarction Names Nature Nervous System Physiology Nitric Oxide Outcome Study Oxidation-Reduction Oxides Parents Pathogenesis Pathway interactions Patients Peptidyl-Dipeptidase A Pharmaceutical Preparations Pharmacologic Substance Phase Plants Production Property Protective Agents Qualifying Reaction Reporting Research Design Risk Factors Role Safety Series Serum Specificity Staging Stroke Structure Sulfhydryl Compounds Sulfur Superoxides Technology Testing Therapeutic Therapeutic Effect Thioctic Acid Time Toxic effect Work base clinically relevant cofactor design dithiol drug candidate drug discovery enzyme activity glucose uptake hypertension treatment improved in vitro Assay in vitro Model in vivo in vivo Model molecular modeling novel pre-clinical prototype public health relevance simulation small molecule therapy development vascular inflammation

项目摘要

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.

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 可诱导体重减轻、降低胆固醇、增加葡萄糖摄取、减少炎症分子的表达并改善血管功能。我们建议通过开发一类新型的 ALA 衍生治疗分子来挖掘 ALA 衍生物用于抗高血压治疗的潜力。我们对原型化合物 INV 65-05 进行的初步体内和体外研究令人鼓舞，并表明这种方法具有优点。因此，我们计划对基于 ALA 的疗法进行合成和表征，并在一年内提出三个具体目标。在具体目标 1a 中，我们计划通过模拟研究来优化结构，并且我们将合成和表征源自天然 ALA 的小分子。在具体目标 1b 中，我们将测试 ACE 抑制功能，并使用体外抗氧化作用和内皮保护测定来确定所选化合物的功效。在具体目标 2a-c 中，我们将使用实验动物模型（自发性高血压大鼠中风倾向模型）研究目标 1 中确定的 2 种精选多功能化合物在降低高血压方面的体内功效。我们将评估这些药物在减少血管炎症、内皮保护、心脏和肺中 ACE 活性、主动脉中超氧化物生成方面的具体效果。在具体目标 3 中，我们将进一步将从目标 1 衍生的先导分子修饰为“一氧化氮”释放药物，并建议测试其在 NO 释放方面的功效以及体外测定。这项科学提案的成功完成将创造出一类具有独特治疗效果的新型分子。将通过第二阶段拨款确定主要候选药物，并对其药代动力学、安全性和毒性进行进一步测试。然后，这将导致向 FDA 提交 IND 申请以执行 I/II 期临床试验。公共卫生相关性：高血压影响着数百万美国成年人，是心肌梗塞、中风、心力衰竭和肾衰竭的主要危险因素。。 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 可诱导体重减轻、降低胆固醇、增加葡萄糖摄取、增加谷胱甘肽、减少炎症分子的表达并改善血管功能。该提案的目的是设计、合成和表征一类新型生物相容性分子，其基于 ALA 的特定修饰，具有多功能治疗作用和理想的药代动力学特性。拟议的衍生物将具有 ACE 抑制特性、降低血压、抗氧化作用和“一氧化氮”释放功能，并通过体外和体内模型进一步研究它们的作用。这项研究的结果将有助于进一步推进此类分子的商业开发。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Methoxyphenol derivatives as reversible inhibitors of myeloperoxidase as potential antiatherosclerotic agents.

DOI：
10.4155/fmc-2019-0080
发表时间：
2019-11
期刊：
Future medicinal chemistry
影响因子：
4.2
作者：
Premkumar Jayaraj;C. Narasimhulu;A. Maiseyeu;Rekha Durairaj;Shashidhar N. Rao;S. Rajagopalan;S. Parthasarathy;Rajagopal Desikan
通讯作者：
Premkumar Jayaraj;C. Narasimhulu;A. Maiseyeu;Rekha Durairaj;Shashidhar N. Rao;S. Rajagopalan;S. Parthasarathy;Rajagopal Desikan