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.

药物和药理探针的设计和开发：药物设计和开发部门的目标是开发针对与衰老相关疾病的病理生理学关键步骤的新型药物，特别关注神经系统疾病，例如阿尔茨海默氏病（AD）和中风，以及全身性疾病，如糖尿病。 1.阿尔茨海默病：正在开发三个系列的药物来治疗阿尔茨海默病。乙酰胆碱酯酶 (AChE)、丁酰胆碱酯酶 (BChE) 和淀粉样蛋白-β 肽 (Ab) 生成的选择性抑制剂。 1.1.胆碱酯酶抑制剂：开发的化合物可以最佳地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。涉及化学、X射线晶体学、生物化学和药理学的广泛研究导致了新化合物的设计和合成，以差异性地抑制大脑或外周中的AChE或BChE，以达到最佳持续时间，从而可能治疗多种疾病，例如如AD、重症肌无力和化学战预防剂。 1.1A。 AChE：我们正在开发众多新型合成的 AChE 抑制剂中的两种，用于治疗 AD；具体来说，纯非竞争性抑制剂、苯酚酚和托丝氨酸。两者都是毒扁豆碱的苯基氨基甲酸酯，对 AChE 的选择性是 BChE 的 70 倍和 190 倍。与现有的 AD 治疗药物相比，它们具有良好的毒理学特征，并能显着增强动物模型的认知能力（与 NIA 的 Donald Ingram 博士合作进行）。它们具有较长的可逆酶抑制持续时间和较短的药代动力学半衰期。这减少了给药频率，减少了体内药物暴露，并最大限度地减少了药物作用对老年人常见的药物代谢个体差异的依赖性。与 Axonyx Inc.（纽约州纽约市）合作，迄今为止已完成三项临床试验，以评估苯酚在健康人群中的安全性、最大耐受剂量 (MTD)、药代动力学 (PK)、药效学 (PD) 和功效概况。老年人和 AD 受试者。其临床开发和评估将在一项正在进行的 AD 2 期试验和两项 3 期试验中继续进行。 1.1B。 BChE：在正常大脑中，约 80% 的胆碱酯酶活性以 AChE 形式存在，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相关。动力学证据表明 BChE 在水解过量的 ACh 中发挥作用。然而，在晚期 AD 中，受影响大脑区域的 AChE 活性降低至正常水平的 15%，而 BChE 活性则增加。 AD 中 BChE 与 AChE 的正常比例变得不匹配，导致已经耗尽的 ACh 水平过度代谢。第一个可用的可逆且高效的 BChE 抑制剂已经合成，并正在进行临床前评估，以评估其作为 AD 候选药物的潜力。正在进行的研究主要集中在认知和 AD 的分子机制上。 1.2.与 AD 相关的分子事件：降低潜在毒性的淀粉样β肽 (Ab) 水平已成为 AD 的重要治疗目标。该目标的关键目标是影响抗体前体蛋白 (APP) 表达和加工的因素。我们的研究表明，苯酚可降低体内和组织培养中的 APP 和 Ab 水平，且无毒性。该活性与其胆碱酯酶作用无关，但属于转录后活性：降低 APP 蛋白水平而不影响 mRNA 水平。这是通过 APP mRNA 的 5'-非翻译区 (UTR) 介导的。目前的研究正在表征所涉及的机制，并将重点放在降低 APP 水平作为降低 Ab 肽的一种方式的药物的设计和合成中。 2.中风和帕金森病：目前用于治疗中风和帕金森病的药物可以暂时缓解症状，但不能阻止细胞死亡。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共同特征，并且是导致细胞凋亡的生化级联的看门人。我们最近设计并合成了一系列新型四氢苯并噻唑和恶唑类似物，可抑制 p53 活性。目前正在组织培养和动物模型中评估化合物的神经保护作用（合作​​者：Mattson 和 Ovadia 博士），以选择有潜力作为候选药物进行评估的药物。 3、糖尿病：2型糖尿病是老年人的多发病。目前的治疗效果并不令人满意。我们的药物设计目标是胰高血糖素样肽-1 (GLP-1) 受体 (R)。 GLP-1 是响应食物而从肠道分泌的，是一种有效的促分泌剂 ?它与胰腺 β 细胞上的 GLP1R 结合，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 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 型糖尿病的临床研究中。结合了 GLP-1 和 Ex-4 最佳特征的新型嵌合肽也已被设计出来，并正在各种模型中进行临床前评估。我们正在描述 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，可保护神经元细胞免受氧化和 Ab 诱导的细胞死亡。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的体内研究。目前的研究重点是选择用于临床评估的药物。 4.炎症：炎症是神经退行性变的一个重要特征，也发生在许多全身性疾病中。我们的目标是细胞因子 TNF-α。新型、有效的 TNF-α 抑制剂正在沙利度胺的基础上合成。在细胞培养研究中，它们通过 3'-UTR 减少转录后 TNF-α 的合成。这些正在经典动物模型中进行评估，以帮助选择治疗肌萎缩侧索硬化症等疾病的临床候选者。