Design And Development Of Experimental Therapeutics

实验疗法的设计和开发

• 批准号: 8736516
• 负责人: Nigel H. Greig
• 金额: $ 95.82万
• 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/8736516
• 关键词: 5' Untranslated Regions; Acetylcholine; Acetylcholinesterase; Acetylcholinesterase Inhibitors; Acute; Affect; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Biochemical; Biochemistry; Brain; Brain region; Canis familiaris; Cell Death; Cell model; Chemical Warfare; Chemistry; Cholinesterase Inhibitors; Cholinesterases; Chronic; Chronic Disease; Clinic; Clinical; Clinical Drug Development; Clinical Investigator; Clinical Research; Clinical Trials; Cognition; Collaborations; Craniocerebral Trauma; Development; Diabetes Mellitus; Disease; Disease Progression; Distant; Drug Design; Drug Formulations; Drug Kinetics; Drug Targeting; Elderly; Embolism; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Event; Extramural Activities; Failure; Functional disorder; Generations; Genus Cola; Goals; Health; Human; Inflammation; Investigation; Kinetics; Laboratories; Measurement; Mediating; Messenger RNA; Metabolism; Methods; Modeling; Molecular; Myasthenia Gravis; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurons; Neurotransmitters; New Agents; Oxazoles; Parkinson Disease; Pathway interactions; Peptides; Pharmaceutical Preparations; Pharmacology; Phase; Phenylcarbamates; Plasma; Pre-Clinical Model; Process; Production; Protein Precursors; Proteins; Research; Risk; Role; Safety; Scientist; Series; Site; Stream; Stroke; Symptoms; System; Systemic disease; Testing; Thalidomide; Therapeutic; Time; Toxic effect; Translating; Translational Regulation; Translational Research; Translations; Traumatic Brain Injury; Tumor Necrosis Factor-alpha; United States National Institutes of Health; Up-Regulation; Vertebral column; X-Ray Crystallography; alpha synuclein; analog; base; cholinergic; cytokine; design; drug candidate; drug development; drug discovery; human TNF protein; in vivo; in vivo Model; inhibitor/antagonist; interest; lenalidomide; nervous system disorder; neuropsychiatry; novel; phase 1 study; phenserine; pre-clinical; preclinical study; pressure; prevent; prophylactic; protein misfolding; regenerative; sarcopenia; tau Proteins; tool; transcription factor; treatment strategy; tumor necrosis factor-alpha inhibitor

1. Alzheimers Disease: Three series of agents are being developed to treat AD. Selective inhibitors of amyloid-beta peptide (abeta) production and inhibitors of the enzymes acetylcholinesterase (AChE) and butrylcholinesterase (BChE) 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. 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 Abeta peptide (collaborators: Drs. Lahiri, Sambamurti, Rogers). The compound, Posiphen, has advanced to clinical trials and backup compounds are being assessed to define molecular mechanisms underpinning activity. Posiphen in a phase 1 proof of concept clinical trial was well tolerated and effectively lowered 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 number of misfolded proteins, including alpha-synuclein. Hence Posiphen and metabolites are being assessed in cellular and animal models of Parkinson's disease as well as 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). 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 the brain or periphery for an optimal duration for the potential treatment of a variety of disorders (AD, myasthenia gravis, and as chemical warfare prophylactics_ (collaborators: Drs. Becker, Lahiri, Kamal, Reale, Sambamurti, Shafferman, Descamp). Also, 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 has been undertaken. Novel phenylcarbamates were developed that are 70- to 190-fold selective for AChE vs. BChE that have favorable toxicologic profiles and robustly enhance cognition in animal models. They induce reversible enzyme inhibition. In collaborative studies phenserine was translated into clinical trials where actions on cognition and levels of CSF and plasma Abeta have been assessed in AD (collaborators: Drs. Becker, Nordberg, Friedhoff, Winblad, Sambamurti, Lahiri, Bruinsma). Generation of a slow release formulation has been undertaken and is currently being assessed in dogs - for planned human studies to impact cognition and modify brain Abeta levels (Collaborators, Drs. Becker, Chigurupati, Flanagan, Araujo) 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 associated 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 have been synthesized and appear favorable in AD preclinical models. Bisnorcymserine has been advanced through required preclinical studies and into clinical phase 1 studies where its safety, pharmacokinetics aand -dynamics are being assessed (collaborators: Drs. Kapogiannis, Maccecchini, Moaddel, Lahiri, Kamal) 1.3. Utilizing the compounds generated 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 select cholinergic compounds. 2. Stroke, Parkinsons disease (PD), brain trauma: 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 several neurodegenerative disorders, and is a gate keeper to the biochemical cascade that leads to apoptosis. We have developed novel tetrahydrobenzothiazole and 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 select ones of potential as clinical candidates. Agents have demonstrated potent activity in models of stroke, AD, PD, and are being assessed in other disorders - including traumatic brain injury (TBI) - to define their optimal use. 3. Inflammation is a critical feature of neurodegeneration as well as numerous systemic disorders. Our target is the cytokine, TNF-alpha. We have developed novel, potent TNF-alpha inhibitors on the backbone of thalidomide, lenalidomide and pomalidomide. They reduce TNF-alpha synthesis post-transcriptionally, via its 3-UTR, in cellular studies. They are being assessed in vivo to define time- and concentration inhibition of TNF-alpha systemically and in brain. Upto 90% inhibition can be achieved in either compartment. Classical animals models are be utilized to aid the selection of a clinical cadidate for chronic diseases such as AD, PD, TBI, ALS, stroke, embolism and sarcopenia (collaborators: Drs. Rosi, Bosetti, Pick, Hoffer, Wang, DeCabo, Levis, Chigurupati, Starke). 4. 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 (Kola & Landis, Nature Rev Drug Discov 3:711-5, 2004). 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, particularly in AD.

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。淀粉样β肽 (abeta) 产生的选择性抑制剂以及乙酰胆碱酯酶 (AChE) 和丁酰胆碱酯酶 (BChE) 的抑制剂 1.1.与 AD 相关的分子事件：降低潜在毒性的淀粉样β肽 (Abeta) 水平已成为 AD 的重要治疗目标。实现这一目标的目标是影响 Abeta 前体蛋白 (APP) 表达和加工的因素。我们的研究已经产生了可以降低神经元培养物和动物模型大脑中 APP 和 Abeta 水平的化合物，且无毒性。该活性独立于胆碱能作用，但属于转录后活性：通过翻译调节降低 APP 蛋白水平而不影响 mRNA 水平。这部分是通过 APP mRNA 的 5 个非翻译区 (UTR) 介导的。目前的研究正在表征所涉及的机制，并重点关注降低 APP 水平的药物的设计和合成，作为降低 Abeta 肽的一种方式（合作者：Lahiri、Sambamurti、Rogers 博士）。该化合物 Posiphen 已进入临床试验，正在评估备用化合物，以确定支持活性的分子机制。 Posiphen 在 1 期概念验证临床试验中具有良好的耐受性，并有效降低 APP、Abeta、tau 和其他关键 AD CSF 标志物（合作者：Maccecchini 博士）。 最近的平行研究（合作者：Rogers、Lahiri、Sambamurti、Maccecchini 博士）表明 Posiphen 具有更广泛的作用，可以影响许多错误折叠的蛋白质，包括 α-突触核蛋白。因此，Posiphen 及其代谢物正在帕金森病以及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，以获得最佳持续时间，从而可能治疗各种疾病（AD、重症肌无力，以及化学战预防剂_（合作者：Becker、Lahiri、Kamal、Reale、Sambamurti、Shafferman、Descamp 博士）。高选择性 BChE 抑制剂已被开发出来，以确定这种酶在健康、衰老和疾病期间在大脑中的作用。 1.2A。 AChE：已开发出长效、中枢活性、选择性的 AChE 抑制剂，以确定其在健康和疾病中的作用，并将化合物纳入临床研究。已经对 eserine 模板进行了广泛的化学研究。我们开发了新型苯基氨基甲酸酯，其对 AChE 的选择性是 BChE 的 70 至 190 倍，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。它们诱导可逆的酶抑制。在合作研究中，苯酚酚被转化为临床试验，在 AD 中评估其对认知以及 CSF 和血浆 Abeta 水平的作用（合作​​者：Becker、Nordberg、Friedhoff、Winblad、Sambamurti、Lahiri、Bruinsma 博士）。缓释制剂的生成已经开始，目前正在狗身上进行评估 - 用于计划的人类研究，以影响认知和改变大脑 Abeta 水平（合作者，Becker、Chigurupati、Flanagan、Araujo 博士） 1.1B。 BChE：在健康的大脑中，80%的胆碱酯酶活性以AChE的形式存在，20%是BChE。 AChE 活性主要集中在神经元中，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。在晚期 AD 中，受影响大脑区域的 AChE 活性下降至正常水平的 15%，而 BChE 活性则上升 2 倍。 AD 中正常的 BChE/AChE 比例变得不匹配，导致已经耗尽的 ACh 过度代谢。第一个可逆的、具有中枢活性的 BChE 抑制剂已经合成，并且在 AD 临床前模型中表现出良好的效果。双去甲丝氨酸已通过所需的临床前研究并进入临床 1 期研究，正在评估其安全性、药代动力学和动力学（合作者：Kapogiannis、Maccecchini、Moaddel、Lahiri、Kamal 博士） 1.3.利用上面生成的化合物，胆碱能系统与炎症之间的关系在健康和疾病中得到表征（合作者：Reale 博士、Kamal）。我们最近的研究表明，AD 中的胆碱能抗炎途径受到损害，但可以通过选择胆碱能化合物有效地“重置”。 2.中风、帕金森病(PD)、脑外伤：目前使用的药物可以暂时缓解症状，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。我们开发了新型四氢苯并噻唑和恶唑类似物，可抑制 p53 活性。目前正在对细胞和动物模型中的神经保护/再生作用进行评估（合作者：Pick、Hoffer、Wang、Luo 博士），以选择有潜力的临床候选药物。这些药物已在中风、AD、PD 模型中表现出有效的活性，并且正在其他疾病（包括创伤性脑损伤 (TBI)）中进行评估，以确定其最佳用途。 3. 炎症是神经变性以及许多全身性疾病的一个关键特征。我们的目标是细胞因子 TNF-α。我们在沙利度胺、来那度胺和泊马度胺的基础上开发了新型、强效的 TNF-α 抑制剂。在细胞研究中，它们通过 3-UTR 减少转录后 TNF-α 的合成。正在对它们进行体内评估，以确定全身和大脑中 TNF-α 的时间和浓度抑制。任一隔室均可实现高达 90% 的抑制。利用经典动物模型来帮助选择慢性疾病的临床候选者，例如 AD、PD、TBI、ALS、中风、栓塞和肌少症（合作者：Rosi、Bosetti、Pick、Hoffer、Wang、DeCabo、Levis 博士） ，奇古鲁帕蒂，斯塔克）。 4. 神经精神疾病中实验药物的临床转化和评估：尽管近年来在理解疾病的可能机制方面取得了有希望的进展，但临床研究人员仍然在努力解决方法和实践，这些方法和实践太容易受到测量误差、偏见和远离研究地点的粗心的影响。申办者，以及尽快进入人体试验的商业压力——这一优先事项被认为导致临床前研究经常不充分，并被怀疑是人体临床试验失败的一个原因。因此，药物发现/开发被认为因缺乏疗效或安全性受损而面临很大的失败风险。 进入临床开发的所有新药物中只有不到 11% 进入市场（Kola & Landis, Nature Rev Drug Discov 3:711-5, 2004）。对于神经系统药物，流失率还要高得多，不到 7%。 为了了解和优化临床开发，正在严格审查和评估影响流程并产生 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临床药物开发流程的合理方法，以帮助降低目前过高的损耗率，特别是在 AD 领域。