Design And Development Of Experimental Therapeutics

实验疗法的设计和开发

• 批准号: 7732195
• 负责人: Nigel H. Greig
• 金额: $ 94.34万
• 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/7732195
• 关键词: 5' Untranslated Regions; Abeta synthesis; Acetylcholine; Acetylcholinesterase; Acetylcholinesterase Inhibitors; Acute; Affect; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Animal Model; Apoptosis; Binding; Biochemical; Biochemistry and Pharmacology Cancer Activity; Biological; Brain; Brain region; Butyrylcholinesterase; Cell Death; Cells; Chemical Warfare; Chemistry; Cholinergic Agents; Cholinesterase Inhibitors; Cholinesterases; Chronic; Chronic Disease; Clinic; Clinical; Clinical Research; Clinical Trials; Clinical assessments; Cognition; Collaborations; Coupled; Craniocerebral Trauma; Cultured Cells; Development; Diabetes Mellitus; Disease; Dose; Drug Addiction; Drug Design; Drug Exposure; Drug Kinetics; Drug effect disorder; Elderly; Enzyme Inhibition; Enzymes; Evaluation; Event; Extramural Activities; Food; Frequencies; Functional disorder; GLP-I receptor; Glucose; Goals; Half-Life; Health; Hydrolysis; Individual; Industry; Inflammation; Japan; Kinetics; Laboratories; Mediating; Messenger RNA; Metabolism; Modeling; Molecular; Myasthenia Gravis; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neuroglia; Neurons; Neurotransmitters; Non-Insulin-Dependent Diabetes Mellitus; Oxazoles; Parkinson Disease; Peptides; Peripheral Nerves; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phenylcarbamates; Physostigmine; Plasma; Process; Property; Protein Precursors; Proteins; Research; Rodent; Role; Scientist; Series; Stroke; Structure of beta Cell of islet; Symptoms; System; Systemic disease; TP53 gene; Testing; Thalidomide; Therapeutic; Time; Toxic effect; Transcriptional Activation; Translating; Translations; Traumatic Brain Injury; Tumor Necrosis Factor-alpha; United States National Institutes of Health; Up-Regulation; Variant; Vertebral column; X-Ray Crystallography; analog; base; cholinergic; cytokine; design; drug development; drug metabolism; exenatide; glucagon-like peptide 1; human TNF protein; in vivo; inhibitor/antagonist; insulin secretion; interest; neuroprotection; novel; phenserine; pre-clinical; preclinical study; prevent; prophylactic; response; therapy development; tissue culture; tolserine; tool; transcription factor; tumor necrosis factor-alpha inhibitor

1. Alzheimers Disease: Three series of agents are being developed to treat AD. Selective inhibitors of acetylcholinesterase (AChE), of butyrylcholinesterase (BChE), and of amyloid-beta peptide (Abeta) 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 (collaborators: Drs. Brossi, Lahiri, Shafferman, Sambamurti, Descamp). In addition, specific and highly selective BChE inhibitors have been designed to characterize the role of this enzyme in brain during health, aging and disease. 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. They have a favorable toxicologic profile and robustly enhance cognition in animal models (collaborator Dr. Ingram). 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 industry, phenserine translated from the laboratory and into clinical trials where actions on cognition and levels of CSF and plasma Abeta have been assessed in mild to moderate AD (collaborators: Drs. Nordberg, Sambamurti, Lahiri). In parallel studies in collaboration with Dr. Utsuki (LSU), Dr. Irie (Kumomoto Univ., Japan) a transdermal patch has been developed to maintain steady-state optimal drug levels and maximize dosing compliance. 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 with a focus to advance a BChE inhibitor to clinic assessment. The selective BChE inhibitor, (-)-bisnorcymserine, has been chosen and is advancing through required preclinical studies. Additional studies are utilizing these valuable agents to define the role of BChE in brain in health, aging and disease (collaborators: Drs. Klein, Lahiri) 1.2. Molecular events associated with AD: The reduction in levels of the potentially toxic amyloid-beta peptide (Abeta) has emerged as an important therapeutic goal in AD. Key targets for this goal are factors that affect the expression and processing of the Abeta precursor protein (APP). Our studies show that phenserine, reduces APP and Abeta 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 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, Giordano, Utsuki). The compound, posiphen, has advanced to clinical trials and backup compounds are being assessed to undertsand molecular mechanisms underpinning activity. A series of new compounds has been designed that combine actions on Abeta with those on AChE or BChE at the same optimal concentration 2. Stroke, Parkinsons disease (PD), brain trauma: Drugs currently used 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 (programmed cell death). 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, Pick, Hoffer, Wang) to select agents of potential for evaluation as drug candidates. Compounds of this calss have demonstrated biological activity in cellular andor animal models of stroke, AD and PD, thet are being assessed in other neurodegenerative diseases to define their optimal use. 3. Diabetes: Type 2 diabetes is a prevalent disease in the elderly. Present treatments are unsatisfactory. Our target for drug design is the glucagon-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 GLP-1R on pancreatic beta-cells to induce glucose-dependent insulin secretion, thereby controling plasma glucose levels. We are developing long-acting GLP-1 analogues (collaborators: Drs. Egan, Mattson). 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, as it is found present in brain and peripheral nerve. GLP-1 analogues possess neurotrophic properties and protect neuronal cells from oxidative and Abeta-induced cell death. Neuroprotection in cell culture translated to in vivo studies in classical rodent neurodegeneration models, which include AD and peripheral neuropathy. 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 vivo to define time- and concentration inhibition of TNF-alpa systemically as well as in brain. Upto 90% inhibition can be achieved in either compartment. Classical animals models are be utilized to aid in the selection of a clinical cadidate for chronic diseases such as amyotrophic lateral sclerosis and PD, as well as acute events such as head trauma (collaborators: Drs. Pick, Hoffer, Wang, Utsuki, Ingram Gabbita).

项目成果

Novel p53 inactivators with neuroprotective action: syntheses and pharmacological evaluation of 2-imino-2,3,4,5,6,7-hexahydrobenzothiazole and 2-imino-2,3,4,5,6,7-hexahydrobenzoxazole derivatives.

• DOI: 10.1021/jm020044d
• 发表时间: 2002-10
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: XiaoXiang Zhu;Qian-sheng Yu;R. Cutler;C. Culmsee;H. Holloway;D. Lahiri;M. Mattson;N. Greig

Syntheses of tetrahydrofurobenzofurans and dihydromethanobenzodioxepines from 5-hydroxy-3-methyl-3H-benzofuran-2-one. Rearrangement and ring expansion under reductive conditions on treatment with hydrides.

由 5-羟基-3-甲基-3H-苯并呋喃-2-酮合成四氢呋喃苯并呋喃和二氢甲烷苯并二氧杂环己烷。

• DOI: 10.1021/jo0503052
• 发表时间: 2005
• 期刊: The Journal of organic chemistry
• 作者: Luo,Weiming;Yu,Qian-Sheng;Holloway,HaroldW;Parrish,Damon;Greig,NigelH;Brossi,Arnold
• 通讯作者: Brossi,Arnold

Characterization of the human beta-secretase 2 (BACE2) 5'-flanking region: identification of a 268-bp region as the basal BACE2 promoter.

人 β 分泌酶 2 (BACE2) 5 侧翼区域的表征：鉴定 268 bp 区域作为基础 BACE2 启动子。

• DOI: 10.1385/jmn:29:1:81
• 发表时间: 2006
• 期刊: Journal of molecular neuroscience : MN
• 作者: Maloney,Bryan;Ge,Yuan-Wen;Greig,NigelH;Lahiri,DebomoyK
• 通讯作者: Lahiri,DebomoyK

Tomographic visualization of cholinesterase.

胆碱酯酶的断层扫描可视化。

• DOI: 10.1002/ana.20926
• 发表时间: 2006
• 期刊: Annals of neurology
• 影响因子: 11.2
• 作者: Kuljis,RodrigoO;Darvesh,Sultan;Greig,NigelH;Geula,Changiz
• 通讯作者: Geula,Changiz

The glucagon-like peptides: a new genre in therapeutic targets for intervention in Alzheimer's disease.

胰高血糖素样肽：干预阿尔茨海默病的治疗靶点的新类型。

• DOI: 10.3233/jad-2002-4605
• 发表时间: 2002
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Perry,TracyAnn;Greig,NigelH
• 通讯作者: Greig,NigelH