Pro-inflammatory cytokine lowering anti-inflammatory drugs

降低促炎细胞因子的抗炎药

• 批准号: 10252567
• 负责人: Nigel H. Greig
• 金额: $ 211.57万
• 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/10252567
• 关键词: 3xTg-AD mouse; Acute; Adult; Adverse effects; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Animal Model; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Appearance; Automobile Driving; Back; Behavioral; Bilirubin; Blood Vessels; Brain; COVID-19; Cell Death; Cell Transplantation; Cell model; Cerebrovascular system; Chickens; Chronic; Clinic; Clinical; Clinical Research; Clinical Trials; Cognitive deficits; Complex; DNA Damage; Degenerative Disorder; Dementia; Deposition; Detection; Development; Disease; Disease Progression; Dose; Drug Kinetics; Drug Targeting; Elderly; Elements; Embryo; Epithelial Cells; Evaluation; Event; Excision; Failure; Generations; Genes; Genetic Transcription; Growth; Human; Image Analysis; Impaired cognition; Impairment; Infiltration; Inflammation; Inflammatory; Interruption; Intervention; Legal patent; Libraries; Lipid Peroxidation; Lung; Lymphocyte; MAPT gene; Maintenance; Mediating; Messenger RNA; Microglia; Mitochondrial DNA; Modeling; Modification; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurologic; Neurologic Dysfunctions; Neurology; Neurons; Oxidants; Oxidative Stress; Parkinson Disease; Pathologic; Pathology; Peripheral Nervous System Diseases; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Physiological; Plasma; Positron-Emission Tomography; Production; Proteins; Psychiatry; Reactive Oxygen Species; Reporting; Rodent; Rodent Model; Role; Sedation procedure; Series; Source; Stroke; Structure-Activity Relationship; Symptoms; Synthesis Chemistry; TNF gene; Teratogens; Thalidomide; Time; Toxic effect; Toxicology; Traumatic Brain Injury; Vertebral column; Virus Diseases; Zebrafish; aging brain; analog; antiangiogenesis therapy; body system; cerebral atrophy; clinical translation; combat; coronavirus disease; course development; cytokine; cytokine release syndrome; effective therapy; efficacy evaluation; entorhinal cortex; in utero; in vivo; mouse model; nervous system disorder; neuroinflammation; neuron loss; neuropathology; neurotoxic; normal aging; novel; pomalidomide; pre-clinical; preclinical study; protein aggregation; protein oligomer; proteostasis; resilience; response; screening; tau Proteins; tau-1; treatment strategy

Tumor necrosis factor-alpha (TNF) is one of the primary pro-inflammatory cytokines synthesized and released by microglial cells with physiological and pathological roles. Once TNF is released, it may initiate a self-propagating cycle of unchecked inflammation (Frankola et al., CNS Neurol Disord Drug Targets 10:391-403, 2011). Pharmacological intervention to interrupt this cycle may be of significant benefit in the setting of neuroinflammation-mediated diseases. In 1993, Moreira et al., (J Exp Med 177:1675-80, 1993) described a series of studies showing that the drug thalidomide (THAL) was able to lower TNF protein levels post-transcriptionally by accelerating degradation of its mRNA. Unfortunately THAL is not a particularly potent TNF lowering agent induces serious teratogenic adverse effects to embryos in utero, sedation and peripheral neuropathy at clinical doses. Nevertheless, the observation of THALs TNF lowering activity gave rise to studies to differentiate these actions, understand THALs TNF structure/activity relationship and develop more potent analogs. In principle, the identification of analogs with enhanced anti-TNF activity and reduced teratogenic and neurotoxic effects may provide a viable treatment strategy for CNS neuroinflammatory and other forms of inflammatory disease. Our medicinal chemistry modifications to the backbone of THAL and newer analogs (namely pomalidomide (POM)) are generating an extensive library of novel agents (successfully issued US patents owned by NIA: 7,973,057 and 8,927,725, and U.S. Patent Application No. 62/235,105 filed September 30, 2015). Our focus is identify well-tolerated drug-like compounds with more potent anti-TNF activity from our generated library and develop these as experimental drugs to characterize the role of the neuroinflammatory component in and to treat Alzheimer's disease (AD) and associated disorders. Problem and Focused Aims: AD is a complex disorder that manifests as progressive dementia with few other symptoms. With a long meandering course, AD is associated with deposits of amyloid-B protein (AB) as much as 20 years prior to the development of dementia. It also induces intracellular accumulation of the microtubule-associated protein Tau (MAPT) as neurofibrillary tangles (NFTs) that correlate more closely with the extent of dementia (Baranello et al., Curr Alzheimer Res 12:32-46, 2015). NFTs arise some 10 years after AB and brain atrophy follows after five further years. However, the resilience and redundancy of the brain protects the affected subject from dementia for around five further years after the detection of atrophy by brain image analysis. Experimental drugs and strategies that reduce the generation of AB oligomers and aggregates as well as of phosphorylated-tau have formed, in large part, the basis of treatment strategies thus far developed to combat the development of AD. Whereas these target are considered the initiators of the cascade of events that become self-propagating and then drive AD progression, their toxicity may not be the direct cause of neurodegeneration. This premise may account for the failure of anti-amyloid and anti-tau therapies in clinical AD trials when administered late in the disease course (Becker et al., Nature Rev Drug Discov 13:156, 2014). The presence of soluble and insoluble AB and MAPT can induce microglia activation (McGeer & McGeer, Acta Neuropathol 126:479-97, 2013), and direct evidence of neuroinflammation in AD brain has been shown by in vivo PET imaging (Schuitemaker et al., Neurobiol Aging 34:12836, 2013). Notably, levels of pro-inflammatory cytokines are elevated in plasma and CSF from AD patients, for TNF by as much as 25-fold (Tarkowski et al., J Clin Immunol 19:223-30, 1999). In MCI subjects that progress to develop AD, a rise in CSF TNF levels correlates with disease progression (Tarkowski et al., J Neurol Neurosurg Psychiatry 74:1200-5, 2003). Paralleling this, elevated expression of TNF is reportedwithin the entorhinal cortex of 3xTg-AD mice prior to the appearance of amyloid and tau pathology, and this increase associates with the onset of cognitive deficits in these mice and later neuronal loss (Janelsins et al. J Neuroinflamm 2:23, 2005). We hypothesize that failure of protein homeostasis leads to accumulation of proteins (e.g., A, APOE and MAPT) that induce microglial activation and a proinflammatory M1 response to instigate their removal. The continuing generation of protein (AB, APOE and MAPT) leads to maintenance of a chronic M1 response, an impairment of transition to an anti-inflammatory M2 response (particularly in the aging brain that is already vulnerable to inflammation) with ensuing neuronal impairment observed in the animal models and in preclinical AD that eventually leads to cell death. Proinflammatory cytokines, like TNF, induce vascular changes to allow lymphocyte infiltration that may underpin reported cerebral vasculature leakiness of AD patients and related Tg mouse models. Moreover, TNF induces AB production in cellular and animal AD models, further increasing its accumulation and accelerating the entire cascade. Our focus is to understand the time course of development of neuropathology accumulation of inflammatory cytokines and behavioral deficits in mouse models that may reflect the disease pathology in humans. Our aim is to use these models, together with classical evaluations of pharmcokinetics/dynamics and toxicity evaluations, to aid select out from our agents that potently lower TNF - compounds that can be moved to the clinic to mitigate the neuroinflammatory element in AD and associated disorders. Our studies involve: (i) Synthetic chemistry on the backbones of THAL and POM to generate more potent anti-inflammatory agents that are better tolerated (Luo et al. Bioorg Med Chem 26:1547-59, 2018). (ii) Cellular screening for anti-inflammatory actions (Tweedie et al. J Neuroinflamm 9:106, 2012) (iii) Zebrafish and chicken embryo screening for anti-inflammatory, anti-angiogenesis and toxicology screening (Collaborators: Drs. Vargesson, Figg) (Mahony et al. PNAS 110:12703-8, 2013; Beedie et al. Oncotarget 7:33237, 2016). (iv) Pharmacokinetic/dynamic/toxicological evaluations in acute rodent studies. (v) Efficacy evaluations in both acute and chronic rodent models involving inflammation, cognitive impairment and/or AD and related disorders (Russo et al. J Neurochem. 122:11871-92, 2012; Tweedie et al. J Neuroinflamm 9:106, 2012; Belarbi et al. J Neuroinflamm 9:23, 2012; Starke et al. J Neuroinflammation 11:77, 2014; Baratz et al. J Neuroinflamm 12:45, 2015; Wang et al. J Neuroinflamm 13:168, 2016; Batsaikhan et al. Int J Mol Sci 20(3) pii: E502; Tsai et al., Cell Transplant 28:439-57, 2019). In synopsis: Our focus is to use our novel compounds as agents to understand the time-dependent role of neuroinflammation in AD progression in animal models and, concurrently, to select out the most potent with drug-like features as a new treatment intervention for AD and related disorders, creating a preclinical package both on our best agent as well as on the comparator clinically approved cancer drug, POM (as a back up), to support clinical translation. Notably, the drug target in these proposed studies - elevated levels of TNF - has relevance to AD (with the potential to impact acute and chronic neurological endpoints) and to related CNS and systemic disorders driven by inflammation (for independent review see: Tobinick E; Curr Alzheimer Res. 9:99-109, 2012; Ignatowski T et al., CNS Drugs. 28:679-97, 2014; Clark & Vissel, J Neuroinflamm ;13:236, 2016). We additionally evaluate our TNF lowering agents in other neurological disorders in which an inflammatory state is evident, and for which effective treatments are lacking (such as TBI, stroke and Bilirubin-induced Neurological Dysfunction and COVID-

肿瘤坏死因子- α （Tumor necrosis factor- α， TNF）是小胶质细胞合成和释放的主要促炎因子之一，具有生理和病理作用。一旦TNF被释放，它可能启动一个不受控制的炎症的自我繁殖周期（Frankola等人，中枢神经系统神经疾病药物靶点10:39 -403,2011）。在神经炎症介导的疾病中，中断这一循环的药物干预可能具有显著的益处。1993年，Moreira等（J Exp Med 177:1675- 80,1993）报道了一系列研究表明，药物thalidomide （THAL）能够通过加速其mRNA的降解，在转录后降低TNF蛋白水平。不幸的是，THAL并不是一种特别有效的TNF降低剂，在临床剂量下会对子宫内胚胎、镇静和周围神经病变产生严重的致畸不良反应。然而，对THALs降低TNF活性的观察引起了区分这些作用的研究，了解THALs TNF结构/活性关系并开发更有效的类似物。原则上，鉴定具有增强抗tnf活性和减少致畸和神经毒性作用的类似物可能为中枢神经系统神经炎症和其他形式的炎症性疾病提供可行的治疗策略。我们对THAL骨架和较新的类似物（即pomalidomide (POM)）的药物化学修饰正在生成广泛的新药物库（成功颁发NIA拥有的美国专利：7,973,057和8,927,725，以及2015年9月30日提交的美国专利申请No. 62/235,105）。我们的重点是从我们生成的文库中鉴定具有更强抗tnf活性的耐受性良好的药物样化合物，并将其开发为实验药物，以表征神经炎症成分在阿尔茨海默病（AD）和相关疾病中的作用。