Design And Development Of Experimental Therapeutics

实验疗法的设计和开发

• 批准号: 6667915
• 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/6667915
• 关键词: Alzheimer's disease; Parkinson's disease; aging; brain disorder chemotherapy; cardiovascular agents; cardiovascular disorder chemotherapy; cardiovascular pharmacology; drug design /synthesis /production; drug screening /evaluation; endocrine pharmacology; human subject; human therapy evaluation; hypoglycemic agents; neuropharmacologic agent; neuropharmacology; noninsulin dependent diabetes mellitus; patient oriented research; 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, such as 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 Corp. (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. In blinded, placebo controlled studies, phenserine was well tolerated as a single oral dose of up to 10 mg once or twice daily. In a preliminary 12 week efficacy trial, phenserine 10 mg (BID) possessed a favorable safety profile and improved specific cognitive tasks in volunteers with mild to moderate AD. Its clinical development and evaluation continues. 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 specific 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 (bAPP). Our studies show that phenserine, reduces bAPP and Ab levels in vivo and in tissue culture without toxicity. This activity is unrelated to its action as an anticholinesterase, but is post-transcriptional as it suppresses bAPP protein expression without altering bAPP mRNA levels. This is mediated via the 5' untranslated region (5 UTR) of bAPP mRNA. We have synthesized novel agents to both characterize the target and to selectively and optimally regulate bAPP mRNA translation to reduce Ab synthesis. Preclinical evaluation studies together with further medicinal chemistry is ongoing. 2. Stroke and Parkinson's disease: Drugs currently used in patients with stroke and Parkinson's disease (PD) provide temporary relief of symptoms, but do not prevent the cell death. Our target for drug development is the transcription factor, p53, as its up-regulation has been described as a common feature of several neurodegenerative disorders, and it is a pivotal step in the biochemical cascade that leads to apoptosis. We recently designed and synthesized a novel series of 2-imino-2,3,4,5,6,7-hexahydrobenzothiazole and 2-imino-2,3,4,5,6,7-hexahydrobenzoxazole analogues that inhibit p53 activity. Compounds are currently being assessed for neuroprotective action in tissue culture and in animal models (in collaboration with Dr. Mark Mattson, Laboratory of Neurosciences, NIA) to select agents of potential for evaluation as drug candidates. 3. Diabetes: Type 2 diabetes is a prevalent disease in the elderly, caused by a relative deficiency of insulin and a decrease in insulin action at insulin-sensitive tissues. Present treatments are unsatisfactory. In collaborative studies with Josephine Egan, M.D. (Diabetes Section, LCS, NIA), we have developed long acting and potent analogues of the endogenous peptide, GLP-1, as a potential treatment for diabetes. GLP-1 is secreted from the gut in response to food and is a potent secretagogue (i.e., it is insulinotropic). When given continuously to diabetic subjects or rodents, pharmacological concentrations of GLP-1 maintain blood glucose levels within their normal range. However, its rapid metabolism in humans and rodents limits its potential therapeutic value. Using GLP-1 as a starting point, numerous longer acting peptides were developed and assessed in animal models of diabetes. This research culminated in the development of the peptide, exendin-4 (Ex-4), into clinical studies in type 2 diabetes. Ex-4 is an endogenous peptide from the Gila monster lizard that shares 53% homology with GLP-1 and that potently binds and activate the GLP-1 receptor. Novel, chimeric peptides that combine the best features of GLP-1 and Ex-4 have been designed, synthesized and are under preclinical assessment in a variety of in vitro and in vivo diabetes models. Our recent studies have focused on the role of the GLP-1 receptor in the central and peripheral nervous systems. GLP-1, Ex-4 and specific analogues possess potent neurotrophic properties, and protect neuronal cells from oxidative and Ab-induced cell death. Neuroprotection in tissue culture translated to in vivo studies in a classical rodent cholinergic forebrain lesion model. Current studies are focused on the potential value of specific peptides in the treatment of peripheral neuropathies, such as the one that often accompanies type 2 diabetes. 4. New targets: Classic medicinal chemistry is being undertaken in the development of novel and potent inhibitors of a pharmacophore that reduces TNF-alpha synthesis by post-transcriptional mechanisms; specifically via translational regulation at its 3' UTR. Reductions in the cytokine, TNF-alpha, hold potential in the treatment of AD and a wide variety of auto-immune diseases. Potent agents have been synthesized and assessed in tissue culture studies. Future studies will assesses whether or not potency is translated into in vivo activity and efficacy in classical animal models.

药物和药理探针的设计和开发：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，例如阿尔茨海默氏病（AD）和中风（AD）和中风，以及在系统性疾病中以及在系统性疾病中以及糖尿病患者。 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 Corp.（纽约，纽约）合作，迄今已完成三项临床试验，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。在盲人，安慰剂对照研究中，phenserine的耐受性良好，是每天一次或两次的单一口服剂量。在一项初步的12周疗效试验中，Pheserine 10 mg（BID）具有有利的安全性，并改善了轻度至中度AD的志愿者的特定认知任务。它的临床发展和评估仍在继续。 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，在特定大脑区域中，ACHE活性降至正常水平的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（BAPP）表达和处理的因素。我们的研究表明，Phenserine在体内和组织培养中降低了BAPP和AB水平，而无需毒性。该活性与其作为抗胆碱酯酶的作用无关，但在转录后是因为它抑制了BAPP蛋白表达而不改变BAPP mRNA水平。这是通过BAPP mRNA的5'未翻译区（5 UTR）介导的。我们已经合成了新型药物来表征靶标的又有选择性和最佳调节BAPP mRNA翻译以减少AB合成。临床前评估研究以及进一步的药物化学正在进行。 2。中风和帕金森氏病：目前在中风和帕金森氏病（PD）患者中使用的药物可暂时缓解症状，但不能预防细胞死亡。我们的药物发育目标是转录因子p53，因为它的上调被描述为几种神经退行性疾病的共同特征，这是生化级联反应的关键步骤，导致凋亡。我们最近设计并合成了一系列新型2-imino-2,3,4,5,6,7-己二苯乙烯曲曲唑和2- imino-2,3,4,5,6,7-己二氧二氢苯唑类似类似物，这些类似物抑制p53活性。目前正在评估化合物在组织培养和动物模型中（与NIA神经科学实验室合作的动物模型中的神经保护作用），以选择具有评估潜力的药物作为候选药物。 3.糖尿病：2型糖尿病是老年人的一种普遍疾病，是由胰岛素相对缺乏和胰岛素敏感组织中胰岛素作用降低引起的。目前的治疗不令人满意。在与M.D. Josephine Egan（LCS，NIA）的Josephine Egan合作研究中，我们开发了内源性肽GLP-1的长作用和有效的类似物，作为糖尿病的潜在治疗方法。 GLP-1是从肠道中分泌的，是对食物的响应，是一种有效的秘密（即它是胰岛素）。当连续地给予糖尿病患者或啮齿动物时，GLP-1的药理学浓度将血糖水平保持在其正常范围内。但是，它在人类和啮齿动物中的快速代谢限制了其潜在的治疗价值。使用GLP-1作为起点，在糖尿病动物模型中开发并评估了许多更长的作用肽。这项研究最终导致肽，Exendin-4（EX-4）的开发，用于2型糖尿病的临床研究。 EX-4是来自Gila Monster蜥蜴的内源性肽，与GLP-1共享53％的同源性，可有效结合并激活GLP-1受体。在各种体外和体内糖尿病模型中设计，合成并在临床前评估中，已经设计，合成并在临床前评估中设计，合成并在临床前评估。 我们最近的研究集中在GLP-1受体在中央和周围神经系统中的作用。 GLP-1，EX-4和特定类似物具有有效的神经营养特性，并保护神经元细胞免受氧化和AB诱导的细胞死亡的影响。组织培养中的神经保护转化为经典啮齿动物胆碱能病变模型中的体内研究。当前的研究集中在特定肽在外周神经病治疗中的潜在值，例如通常伴随2型糖尿病的肽。 4。新靶标：经典的药物化学正在开发新型和有效的药效剂，从而通过转录后机制降低TNF-Alpha合成；特别是通过其3'UTR的翻译调节。细胞因子TNF-Alpha的降低在AD治疗和多种自身免疫性疾病方面具有潜力。在组织培养研究中已经合成并评估了有效的药物。未来的研究将评估是否将效力转化为经典动物模型中的体内活性和功效。