Design And Development Of Experimental Therapeutics

实验疗法的设计和开发

• 批准号: 10007334
• 负责人: Nigel H. Greig
• 金额: $ 81.14万
• 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/10007334
• 关键词: 5' Untranslated Regions; Abeta synthesis; Academia; Acetylcholine; Acetylcholinesterase; Acetylcholinesterase Inhibitors; Affect; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Animal Disease Models; Animal Model; Anti-Cholinergics; Anti-inflammatory; Apoptosis; Apoptotic; Astrocytes; Basic Science; Biochemical; Biochemistry; Biological; Biological Markers; Brain; Brain Injuries; Brain region; Cell Death; Cell model; Cells; Chemical Warfare; Chemistry; Cholinesterase Inhibitors; Cholinesterases; Clinic; Clinical; Clinical Drug Development; Clinical Investigator; Clinical Research; Clinical Trials; Clinical assessments; Cognition; Collaborations; Development; Disease; Disease Marker; Disease Progression; Distant; Dose; Down Syndrome; Drug Design; Drug Kinetics; Drug Targeting; Elderly; Elements; Enzyme Inhibitor Drugs; Enzymes; Evaluation; Event; Extramural Activities; Failure; Formulation; Functional disorder; Gatekeeping; Genetic Transcription; Goals; Health; Health Benefit; Human; Impairment; Industry; Inflammation; Investigation; Investigational Therapies; Kinetics; Lead; Legal patent; Licensing; Measurement; Mediating; Messenger RNA; Metabolism; Methods; Molecular; Molecular Target; Myasthenia Gravis; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurons; Neurotransmitters; New Agents; Oxazoles; Parkinson Disease; Pathway interactions; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Phase I Clinical Trials; Phenylcarbamates; Plasma; Pre-Clinical Model; Procedures; Process; Protein Precursors; Proteins; Research; Resources; Rewards; Risk; Role; Safety; Sampling; Series; Site; Stroke; System; TP53 gene; Technology; Testing; Therapeutic; Time; Toxic effect; Toxicology; Translating; Translational Regulation; Translations; Traumatic Brain Injury; Up-Regulation; X-Ray Crystallography; alpha synuclein; analog; behavioral impairment; cholinergic; clinical development; clinical translation; clinically relevant; design; drug candidate; drug development; drug discovery; exosome; in vivo; in vivo Model; inhibitor/antagonist; misfolded protein; multidisciplinary; nervous system disorder; neuron loss; neuropsychiatry; novel; novel therapeutics; off-patent; phase 1 study; phenserine; pre-clinical; pressure; prophylactic; reduce symptoms; regenerative; stroke model; tau Proteins; transcription factor

1. Alzheimers Disease: Three series of agents are being developed to treat AD. Selective inhibitors of amyloid-beta peptide (abeta) production (Posiphen) and inhibitors of the enzymes acetylcholinesterase (AChE) (Phenserine - has has antiapoptotic actions) and butrylcholinesterase (BChE) (Bisnorcymserine). 1.1. Molecular events associated with AD: A reduction in levels of the potentially toxic amyloid-beta peptide (Abeta) has emerged as an important therapeutic goal in AD. Targets to achieve this goal are factors that affect the expression and processing of the Abeta precursor protein (APP). Our studies have generated compounds to lower APP and Abeta levels in neuronal cultures and the brain of animal models without toxicity. This activity is independent of cholinergic action, but is post-transcriptional: lowering APP protein levels without affecting mRNA levels via translational regulation. This is mediated, in part, via the 5-untranslated region (UTR) of APP mRNA. We are characterizing mechanisms involved and focusing on these in the design and synthesis of new agents that lower APP levels as a way of lower Abeta peptide (collaborators: Drs. Lahiri, Sambamurti). Posiphen (aka., ANVS-401) is in clinical trials and a new backup compound has been generated. Posiphen was well tolerated in phase 1 clinical trials, showing target engagement and effectively lowering APP, Abeta, tau and other key AD CSF markers (collaborator: Dr. Maccecchini). Recent parallel studies (collaborator: Drs. Rogers, Lahiri, Sambamurti, Maccecchini) indicate that Posiphen has a broader action that impacts a wide number of misfolded proteins, including alpha-synuclein. Posiphen and metabolites are being assessed in cellular and animal models of Parkinson's disease (PD), Down's syndrome and other neurological disorders. 1.2. Cholinesterase inhibitors: Compounds were developed to optimally augment the cholinergic system in the elderly and raise levels of the neurotransmitter, acetylcholine (ACh). Chemistry, X-ray crystallography, biochemistry and pharmacology studies resulted in the design and synthesis of novel compounds to differentially inhibit either AChE or BChE in the brain or periphery for the potential treatment of a variety of disorders (AD, TBI, myasthenia gravis, and as chemical warfare prophylactics (collaborators: Drs. Becker, Hoffer, Marini, Lahiri, Kamal, Reale, Sambamurti, Descamp). Specific and highly selective BChE inhibitors have been developed to define this enzyme's role in brain during health, aging and disease. 1.2A. AChE: Long-acting, centrally active, selective inhibitors of AChE have been developed to define its role in health and disease and move compounds into clinical studies. Extensive chemistry on the template of eserine was undertaken. Novel phenylcarbamates were developed that are highly selective for AChE vs. BChE, have favorable toxicologic profiles, robustly enhance cognition in animal models and are neurotrophic/protective and anti-inflammatory. Phenserine was translated into clinical trials in AD (collaborators: Drs. Becker, Nordberg, Friedhoff, Winblad, Sambamurti, Lahiri, Bruinsma). A new AD clinical trial is about to start with a new slow-release formulation (Collaborators, Drs. Schneider, Ballard, Becker, Flanagan, Kapogiannis) to reduce neuronal cell death, and involves exosome technology paired with classical markers of disease course. Recent studies show Phenserine is highly effective in protecting against brain injury (stroke and TBI) providing potent anti-apoptotic actions across cellular and in vivo models, and new analogues have been synthesized and are under evaluation. 1.1B. BChE: In healthy brain, 80% of cholinesterase activity is in the form of AChE and 20% is BChE. AChE activity is concentrated chiefly in neurons, and BChE primarily with glial cells. Kinetic evidence indicates a role for BChE, in hydrolysing excess ACh. In advanced AD, AChE activity declines to 15% of normal levels in affected brain regions, whereas BChE activity rises 2-fold. The normal BChE/AChE ratio becomes mismatched in AD causing excess metabolism of already depleted ACh. The first reversible, centrally-active BChE inhibitors were synthesized and appear favorable in AD preclinical models. Bisnorcymserine was advanced into clinical phase 1 studies where its safety, pharmacokinetics and -dynamics are being assessed (collaborators: Drs. Kapogiannis, Maccecchini, Lahiri, Kamal) 1.3. With the compounds above, the relationship between the cholinergic system and inflammation is being characterized in health and disease (collaborators: Drs. Reale, Kamal). Our recent studies suggest that the cholinergic anti-inflammatory pathway is compromised in AD, but can potentially be effectively "reset" by phenserine. 2. Stroke, AD, PD, brain trauma, Down's syndrome: Drugs currently used provide temporary relief of symptoms, but do not prevent the occurrence of cell death. Our target for drug design is the transcription factor, p53 and its down-stream effectors. p53 up-regulation is a common feature of many neurodegenerative disorders and a gatekeeper to the biochemical cascade that leads to apoptosis. We developed novel tetrahydrobenzothiazole/oxazole analogs that inhibit p53 activity. Agents are in current assessment for neuroprotective/regenerative actions in cellular and animal models (collaborators: Drs. Pick, Hoffer, Wang, Luo) to define whether neurons can be rescued from apoptotic cell death. Our p53 inactivators demonstrate potent activity in models of stroke, AD, PD, and are in assessment in other disorders - including TBI - to define their optimal use. In parallel with evaluating whether neurons can be rescued from damage and dysfunction by inactivating p53 dependent apoptotic mechanisms that lead to cell death, we have demonstrated the efficacy of phenserine at clinically relevant doses in animal models of TBI and stroke. Its antiapoptotic and anti-inflammatory actions result in reduced neuronal cell death and the mitigation of behavioral impairments across animal models at well tolerated doses 3. Clinical translation and assessment of experimental drugs in neuropsychiatric conditions: Despite promising advances in understanding possible mechanisms of disease in recent years, clinical investigators still struggle with methods and practices too open to effects from measurement errors, biases, carelessness at research sites distant from the sponsor, and with commercial pressures to as quickly as possible enter human trials - a priority that is acknowledged to allow frequently insufficient preclinical investigations and suspected as one cause for failures in human clinical trials. Hence, drug discovery/development is acknowledged as at great risks of failing due to lack of efficacy or compromises to safety. Less than 11% of all new agents that enter clinical development reach the marketplace. For neurological drugs, attrition is considerably higher still, less than 7%. To understand and optimize clinical development the numerous factors that impair the process and generate type 2 errors are being critically reviewed and assessed (Collaborator: Dr. Becker). Rational approaches to optimize the clinical drug development process of neuropsychiatric drugs are being developed to aid reduce the currently too high attrition rate in neurological drug development, and particularly in AD. We are evaluating best procedures in relation to advancing drugs into the clinical development stage, and are evaluating biomarkers available from exosomes - obtained from plasma samples that are enriched for neuronal and/or astrocytic cells (Collaborators: Drs. Kapogiannis, Goetzl, Becker, Schneider, Ballard) - to potentially follow drug-target engagement in brain and alterations in disease course.

1。阿尔茨海默氏病：正在开发三种制剂来治疗AD。淀粉样β肽（ABETA）生产（Posiphen）和乙酰胆碱酯酶（ACHE）的抑制剂的选择性抑制剂（Phenserine-具有抗凋亡作用）和丁烷胆碱酯酶（BCHE）（BCHE）（Bisnorcymserine）。 1.1。与AD相关的分子事件：潜在毒性淀粉样蛋白β肽（ABETA）的水平降低已成为AD的重要治疗目标。实现此目标的目标是影响Abeta前体蛋白（APP）表达和处理的因素。我们的研究已经产生了降低神经元培养物和动物模型大脑的APP和ABETA水平的化合物，而无需毒性。该活性与胆碱能作用无关，但在转录后是：降低APP蛋白水平，而不会通过翻译调节影响mRNA水平。这部分是通过App mRNA的5个非翻译区（UTR）介导的。我们正在表征所涉及的机制，并将其集中在新的代理的设计和合成中，这些新代理将应用程序水平降低为较低的Abeta肽的一种方式（合作者：Lahiri博士，Sambamurti）。 Posiphen（又名ANVS-401）正在临床试验中，并且已经产生了新的备份化合物。 Posiphen在第1阶段临床试验中的耐受性良好，显示了目标参与，并有效地降低了App，Abeta，Tau和其他关键AD CSF标记（合作者：MacCecchini博士）。 最近的平行研究（合作者：Rogers博士，Lahiri，Sambamurti，Maccecchini）表明，Posiphen具有更广泛的作用，会影响包括α-核蛋白在内的广泛错误折叠的蛋白质。 Posiphen和代谢产物正在帕金森氏病（PD），唐氏综合症和其他神经系统疾病的细胞和动物模型中进行评估。 1.2。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。 Chemistry, X-ray crystallography, biochemistry and pharmacology studies resulted in the design and synthesis of novel compounds to differentially inhibit either AChE or BChE in the brain or periphery for the potential treatment of a variety of disorders (AD, TBI, myasthenia gravis, and as chemical warfare prophylactics (collaborators: Drs. Becker, Hoffer, Marini, Lahiri, Kamal，Reale，Sambamurti，descamp）已开发出特定的和高度选择性的BCHE抑制剂，以定义这种酶在健康，衰老和疾病期间的作用。 1.2a。 ACHE：已开发出长效，中心活跃的选择性抑制剂，以定义其在健康和疾病中的作用，并将化合物转移到临床研究中。进行了埃塞林模板上的广泛化学反应。开发了新型的苯基钙化物，它们对ACHE和BCHE具有高度选择性，具有良好的毒性特征，可健全地增强动物模型的认知，并且具有神经营养/保护性和抗炎作用。 Phenserine被转化为AD的临床试验（合作者：Becker博士，Nordberg，Friedhoff，Winblad，Sambamurti，Lahiri，Bruinsma）。一项新的AD临床试验将从新的慢速释放配方开始（合作者，Schneider博士，Ballard，Becker，Flanagan，Flanagan，kapogiannis），以减少神经元细胞死亡，并涉及外泌体技术与疾病课程的经典标记配对。最近的研究表明，Phenserine在保护脑损伤（中风和TBI）方面非常有效，可在细胞和体内模型中提供有效的抗凋亡作用，并且已合成新的类似物并正在评估中。 1.1b。 BCHE：在健康的大脑中，胆碱酯酶活性的80％是ACHE的形式，而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。在晚期AD中，ACHE活性在受影响的大脑区域中下降到正常水平的15％，而BCHE活性上升了2倍。正常的BCHE/ACHE比在AD中不匹配，导致已枯竭ACH的过量代谢。合成了第一个可逆的，中心活跃的BCHE抑制剂，并且在AD临床前模型中看起来有利。双诺菌进入了临床第一阶段研究中，正在评估其安全性，药代动力学和 - 动力学（合作者：Kapogiannis博士，Maccecchini，Maccecchini，Lahiri，Kamal） 1.3。在上面的化合物中，胆碱能系统与炎症之间的关系在健康和疾病中的特征（合作者：卡马尔雷尔博士）。我们最近的研究表明，胆碱能抗炎途径在AD中受到损害，但可能会被Phenserine有效地“重置”。 2.中风，AD，PD，脑创伤，唐氏综合症：当前使用的药物可暂时缓解症状，但不能阻止细胞死亡的发生。我们的药物设计目标是转录因子p53及其下游效应子。 p53上调是许多神经退行性疾病的共同特征，也是导致凋亡的生化级联反应者的守门人。我们开发了抑制p53活性的新型四氢苯甲酸/恶唑类似物。当前对细胞和动物模型中神经保护性/再生作用的评估（合作者：Pick，Hoffer，Wang，Luo），以定义是否可以从凋亡细胞死亡中救出神经元。我们的p53灭活因子在中风，AD，PD模型中表现出了有效的活性，并且正在评估包括TBI在内的其他疾病，以定义其最佳用途。与评估是否可以通过灭活导致细胞死亡的p53依赖性凋亡机制来挽救神经元是否可以从损害和功能障碍中救出，我们已经证明了苯啉在TBI和中风动物模型中临床相关剂量的疗效。它的抗凋亡和抗炎作用导致神经元细胞死亡减少，并以良好的剂量跨动物模型跨动物模型减轻行为障碍 3。神经精神疾病中实验药物的临床翻译和评估：尽管有望在了解近年来了解疾病的可能机制方面取得了希望被怀疑是人类临床试验中失败的原因之一。因此，由于缺乏疗效或对安全性妥协，药物发现/开发被认为是失败的很大风险。 进入临床开发的所有新代理商中，只有不到11％进入市场。对于神经药物，损耗仍然高得多，小于7％。 为了了解和优化临床开发，正在严格审查和评估损害该过程并产生2型错误的众多因素（合作者：Becker博士）。正在开发优化神经精神药物的临床药物开发过程的合理方法，以帮助降低神经药物开发（尤其是AD中）当前过高的损耗率。 We are evaluating best procedures in relation to advancing drugs into the clinical development stage, and are evaluating biomarkers available from exosomes - obtained from plasma samples that are enriched for neuronal and/or astrocytic cells (Collaborators: Drs. Kapogiannis, Goetzl, Becker, Schneider, Ballard) - to potentially follow drug-target engagement in brain and alterations in disease course.