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。阿尔茨海默氏病：正在开发三种制剂来治疗AD。淀粉样β肽（ABETA）的选择性抑制剂和乙酰胆碱酯酶（ACHE）和丁聚胆碱酯酶（BCHE）的抑制剂（ACHE）抑制剂（BCHE） 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。当前的研究表征了所涉及的机制，并将其集中在降低App水平的设计和合成中，这些试剂降低了App水平，作为一种较低的Abeta肽的方式（合作者：Lahiri博士，Sambamurti，Rogers）。该化合物Posiphen已升级为临床试验，并且正在评估备用化合物以定义了基于活性的分子机制。 POSIPHEN在第一阶段的概念验证临床试验中得到了很好的耐受性，并有效地降低了应用程序，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，会影响许多错误折叠的蛋白质，包括α-核蛋白。因此，在帕金森氏病的细胞和动物模型以及其他神经系统疾病中，正在评估Posiphen和代谢产物。 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。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新型化合物的设计和合成，以差异性地抑制大脑中的ACHE或BCHE或BCHE，或者在可能治疗各种疾病的潜在治疗中，以最佳治疗（AD，AD，AD，Myasthenia grampis warfare propfare propfare proshylictor，Les conseriric，lers conserics conceirrics，lers ls concoriric concory conceiralics：lers。 Kamal，Reale，Sambamurti，Shafferman，Descamp）也开发了特定和高度选择性的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。已经进行了埃塞林模板上的广泛化学反应。开发了新型的苯基氨基甲酸酯，对于具有良好的毒性特征并强劲增强了动物模型的认知，对ACHE和BCHE的选择性为70至190倍。它们诱导可逆酶抑制作用。在协作研究中，Phenserine被转化为临床试验，在AD中评估了有关CSF和血浆ABETA认知水平和血浆Abeta水平的行动（合作者：Becker博士，Nordberg，Friedhoff，Winblad，Sambamurti，Lahiri，Lahiri，Lahiri，Bruinsma）。已经进行了缓慢释放的配方，目前正在狗中进行评估 - 计划的人类研究会影响认知和修改脑abeta水平（合作者，贝克尔博士，Chigurupati博士，Flanagan，Araujo） 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。第一个可逆的中心活性BCHE抑制剂已合成，并且在AD临床前模型中看起来有利。双诺菌塞林已通过所需的临床前研究和临床第1阶段研究进行了进步，在该研究中，正在评估其安全性，药代动力学Aand -dynamics（合作者：Kapogiannis，MacCecchini，MacCecchini，Moaddel，Moaddel，Moaddel，Lahiri，Lahiri，Kamal） 1.3。利用上面产生的化合物，胆碱能系统与炎症之间的关系在健康和疾病中被表征（合作者：卡玛尔雷尔博士）。我们最近的研究表明，胆碱能抗炎途径在AD中受到损害，但有效地通过某些胆碱能化合物有效地“重置”了胆碱能。 2.中风，帕金森病（PD），脑外伤：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器的门将。我们已经开发了抑制p53活性的新型四氢苯甲酸苯唑和恶唑类似物。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：Dr. pick，Hoffer，Wang，Luo），以选择潜在的临床候选者。代理在中风，AD，PD模型中表现出了有效的活性，并且正在其他疾病（包括脑外伤（TBI））中进行评估，以定义其最佳用途。 3。炎症是神经变性以及众多全身性疾病的关键特征。我们的靶标是细胞因子TNF-α。我们已经在沙利度胺，勒纳度胺和pomalidomide的骨架上开发了新型的有效TNF-α抑制剂。它们在细胞研究中通过其3-UTR在转录后降低TNF-α合成。它们正在体内评估，以系统和大脑中定义TNF-Alpha的时间和浓度抑制。在任何一个隔间中，最多可抑制90％。经典的动物模型可用于帮助选择诸如AD，PD，TBI，ALS，Stroke，Stroke，Enmolism和Sarcopenia之类的慢性疾病的临床减少症（合作者：Rosi，Boseti，Boseti，Boseti，Pick，Hoffer，Hoffer，Wang，Wang，DeCabo，Levis，Levis，Chigurupati，Chigurupati，Starke）。 4。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可能的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。 进入临床发展的所有新代理商中，只有不到11％到达市场（Kola＆Landis，Nature Rev Drug Discov 3：711-5，2004）。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，以帮助降低当前过高的损耗率，尤其是在AD中。