Design And Development Of Experimental Therapeutics

实验疗法的设计和开发

• 批准号: 6968788
• 负责人: Nigel H. Greig
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6968788
• 关键词: Alzheimer' s disease; Parkinson' s disease; acetylcholinesterase; aging; brain disorder chemotherapy; cardiovascular agents; cardiovascular disorder chemotherapy; cardiovascular pharmacology; cholinesterase inhibitors; drug design /synthesis /production; drug screening /evaluation; endocrine pharmacology; human tissue; hypoglycemic agents; neuropharmacologic agent; neuropharmacology; noninsulin dependent diabetes mellitus; stroke

Design and Development of Drugs and Pharmacologic Probes: The goal of the Drug Design & Development Section is to develop novel agents against pivotal steps involved in the pathophysiology of diseases associated with aging, with particular interest in neurological diseases, exemplified by Alzheimer's disease (AD) and stroke, as well as in systemic diseases, such as diabetes. 1. Alzheimer's Disease: Three series of agents are being developed to treat AD. Selective inhibitors of acetylcholinesterase (AChE), of butyrylcholinesterase (BChE), and of amyloid-beta peptide (Ab) production. 1.1. Cholinesterase inhibitors: Compounds were developed to optimally augment the cholinergic system in the elderly and raise levels of the neurotransmitter, acetylcholine (ACh). Extensive studies involving chemistry, X-ray crystallography, biochemistry and pharmacology resulted in the design and synthesis of novel compounds to differentially inhibit either AChE or BChE in either the brain or periphery for an optimal duration for the potential treatment of a variety of diseases, such as AD, Myasthenia Gravis, and as chemical warfare prophylactics. 1.1A. AChE: Two of our numerous novel synthesized AChE inhibitors are in development for the treatment of AD; specifically, the pure non-competitive inhibitors, phenserine and tolserine. Both are phenylcarbamates of physostigmine that are 70- and 190-fold selective for AChE vs. BChE. Compared to current agents for AD treatment, they have a favorable toxicologic profile and robustly enhance cognition in animal models (undertaken in collaboration with Dr. Donald Ingram, NIA). They possess a long duration of reversible enzyme inhibition, coupled with a short pharmacokinetic half-life. This reduces dosing frequency, decreases body drug exposure and minimizes the dependence of drug action on the individual variations of drug metabolism commonly found in the elderly. In collaboration with Axonyx Inc. (New York, NY), three clinical trials have thus far been completed to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetic (PK), pharmacodynamic (PD) and efficacy profile of phenserine, in healthy elderly and AD subjects. Its clinical development and evaluation continues in one ongoing phase 2 and two phase 3 trials in AD. 1.1B. BChE: In normal brain, some 80% of cholinesterase activity is in the form of AChE and 20% is BChE. AChE activity is concentrated mainly in neurons, while BChE is primarily associated with glial cells. Kinetic evidence indicates a role for BChE, in hydrolysing excess ACh. In advanced AD, however, AChE activity decreases to 15% of normal levels in affected brain regions, whereas BChE activity increases. The normal ratio of BChE to AChE becomes mismatched in AD causing excess metabolism of already depleted levels of ACh. The first available reversible and highly potent BChE inhibitors have been synthesized and are in preclinical assessment to evaluate their potential as AD drug candidates. On going studies are focusing on cognition and the molecular mechanisms underpinning AD. 1.2. Molecular events associated with AD: The reduction in levels of the potentially toxic amyloid-beta peptide (Ab) has emerged as an important therapeutic goal in AD. Key targets for this goal are factors that affect the expression and processing of the Ab precursor protein (APP). Our studies show that phenserine, reduces APP and Ab levels in vivo and in tissue culture without toxicity. This activity is independent of its cholinesterase action, but is post-transcriptional: lowering APP protein levels without affecting mRNA levels. This is mediated via the 5'-untranslated region (UTR) of APP mRNA. Current studies are characterizing mechanisms involved and focusing on these in the design and synthesis of agents that lower APP levels as a way of lower Ab peptide. 2. Stroke and Parkinson's disease: Drugs currently used to treat stroke and PD provide temporary relief of symptoms, but do not prevent the cell death. Our target for drug design is the transcription factor, p53. Its up-regulation is a common feature of several neurodegenerative disorders, and is a gate keeper to the biochemical cascade that leads to apoptosis. We recently designed and synthesized a novel series of tetrahydrobenzothiazole and ?oxazole analogues that inhibit p53 activity. Compounds are in current assessment for neuroprotective action in tissue culture and animal models (collaborators: Drs. Mattson& Ovadia) to select agents of potential for evaluation as drug candidates. 3. Diabetes: Type 2 diabetes is a prevalent disease in the elderly. Present treatments are unsatisfactory. Our target for drug design is the glucagons-like peptide-1 (GLP-1) receptor (R). GLP-1 is secreted from the gut in response to food and is a potent secretagogue ? it binds to the GLP1R on pancreatic beta-cells to induce glucose-dependent insulin secretion, thereby controling plasma glucose levels. We are developing long-acting GLP-1 analogues (collaborator: Dr. Egan). This research aided in the development of the peptide exendin-4 (Ex-4) into clinical studies in type 2 diabetes. Novel chimeric peptides that combine the best features of GLP-1 and Ex-4 have also been designed and are under preclinical assessment in a variety models. We are characterizing the role of the GLP-1R stimulation in the nervous system. GLP-1 analogues possess neurotrophic properties and protect neuronal cells from oxidative and Ab-induced cell death. Neuroprotection in cell culture translated to in vivo studies in classical rodent neurodegeneration models. Current studies are focused on selecting agents for clinical assessment. 4. Inflammation: Inflammation is a critical feature of neurodegereation and also occurs in numerous systemic diseases. Our target is the cytokine, TNF-alpha. Novel, potent TNF-alpha inhibitors are being synthesized on the backbone of thalidomide. They reduce TNF-alpha synthesis post-transcriptionally, via its 3'-UTR, in cell culture studies. These are being assessed in classical animals models to aid in the selection of a clinical cadidate for diseases such as Amyotrophic Lateral Sclerosis.

药物和药理学探针的设计和开发：药物设计与开发部门的目的是开发针对与衰老有关的疾病病理生理学的关键步骤的新型药物，对神经系统疾病特别感兴趣，以阿尔茨海默氏病（AD）和Streoke（AD）和Streoke以及诸如系统性疾病（以及诸如糖尿病）的兴趣。 1。阿尔茨海默氏病：正在开发三个系列以治疗AD。乙酰胆碱酯酶（ACHE），丁酰胆碱酯酶（BCHE）和淀粉样蛋白β肽（AB）产生的选择性抑制剂。 1.1。胆碱酯酶抑制剂：开发化合物是为了最佳增强老年人的胆碱能系统并提高神经递质乙酰胆碱（ACH）的水平。 Extensive studies involving chemistry, X-ray crystallography, biochemistry and pharmacology resulted in the design and synthesis of novel compounds to differentially inhibit either AChE or BChE in either the brain or periphery for an optimal duration for the potential treatment of a variety of diseases, such as AD, Myasthenia Gravis, and as chemical warfare prophylactics. 1.1a。 ACHE：我们众多新型合成的ACHE抑制剂中有两个正在开发AD治疗。具体而言，纯的非竞争性抑制剂，保透明碱和托尔赛因。两者都是Physostigmine的苯基钙化，对于ACHE与BCHE的选择性为70倍和190倍。与目前的AD治疗药物相比，它们具有良好的毒性特征，并在动物模型中强烈增强了认知（与NIA Donald Ingram博士合作进行）。它们具有长时间的可逆酶抑制作用，再加上短的药代动力学半衰期。这会降低给药频率，降低人体药物的暴露，并最大程度地减少药物作用对老年人常见的药物代谢的个体变异的依赖性。与Axonyx Inc.（纽约，纽约）合作，迄今已完成了三项临床试验，以评估健康的老年人和AD受试者的安全性，最大耐受剂量（MTD），药代动力学（PK），药效学（PD）和Phenserine的功效。它的临床开发和评估在AD中的一个正在进行的2阶段和第三阶段试验中继续进行。 1.1b。 BCHE：在正常的大脑中，约80％的胆碱酯酶活性为ACHE，20％为BCHE。 ACHE活性主要集中在神经元中，而BCHE主要与神经胶质细胞有关。动力学证据表明BCHE在水解过量ACH中的作用。然而，在晚期AD中，ACHE活性在受影响的大脑区域中降至正常水平的15％，而BCHE活性增加。 BCHE与ACHE的正常比率在AD中不匹配，导致ACH水平耗尽的过量代谢。首次可用的可逆且高度有效的BCHE抑制剂已合成，并且正在临床前评估中评估其作为AD药物候选者的潜力。进行研究的重点是认知和基于AD的分子机制。 1.2。与AD相关的分子事件：潜在毒性淀粉样蛋白β肽（AB）水平的降低已成为AD中重要的治疗目标。该目标的主要目标是影响AB前体蛋白（APP）表达和处理的因素。我们的研究表明，Phenserine，在没有毒性的情况下，在体内和组织培养中降低了APP和AB水平。该活性与其胆碱酯酶作用无关，但在转录后是：降低APP蛋白水平而不会影响mRNA水平。这是通过App mRNA的5'非翻译区（UTR）介导的。当前的研究正在表征涉及的机制，并将其集中在降低APP水平的药物的设计和合成中。 2。中风和帕金森氏病：目前用于治疗中风和PD的药物可暂时缓解症状，但不能防止细胞死亡。我们的药物设计目标是转录因子p53。它的上调是几种神经退行性疾病的常见特征，并且是导致细胞凋亡的生化级联反应的门将。我们最近设计并合成了一系列新型的四氢苯甲酸苯唑和抑制p53活性的恶唑类似物。在组织培养和动物模型（合作者：Mattson＆Ovadia博士）中的神经保护作用的当前评估中，化合物正在选择评估潜力的药物作为候选药物。 3.糖尿病：2型糖尿病是老年人普遍存在的疾病。目前的治疗不令人满意。我们的药物设计目标是葡萄糖样肽-1（GLP-1）受体（R）。 GLP-1是从肠道中分泌的，以响应食物，并且是一个有力的秘密吗？它与胰腺β细胞上的GLP1R结合，以诱导葡萄糖依赖性胰岛素分泌，从而控制血浆葡萄糖水平。我们正在开发长效的GLP-1类似物（合作者：Egan博士）。这项研究有助于将肽Exendin-4（EX-4）开发到2型糖尿病中的临床研究中。结合GLP-1和EX-4最佳特征的新型嵌合肽也已设计并在各种模型中的临床前评估。我们正在表征GLP-1R刺激在神经系统中的作用。 GLP-1类似物具有神经营养特性，并保护神经元细胞免受氧化和AB诱导的细胞死亡的影响。细胞培养中的神经保护转化为经典啮齿动物神经变性模型中的体内研究。当前的研究集中在选择临床评估的药物上。 4。炎症：炎症是神经残疾人的关键特征，也发生在许多全身性疾病中。我们的靶标是细胞因子TNF-α。新颖的有效TNF-α抑制剂正在甲状酸酯的支柱上合成。它们在转录后通过其3'-UTR在细胞培养研究中降低了TNF-alpha合成。在古典动物模型中评估了这些方法，以帮助选择诸如肌萎缩性侧索硬化症等疾病的临床检查症。