A Novel Small Molecule TNF-alpha Inhibitor as a Disease-Modifying Alzheimer's Disease Drug Treatment

一种新型小分子 TNF-α 抑制剂作为缓解阿尔茨海默病药物治疗的药物

基本信息

批准号：
9466541
负责人：
SOMASUNDAR PRASAD GABBITA
金额：
$ 69.69万
依托单位：
P2D, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9466541
关键词：
ADME Study Acute Address Adverse effects Affect Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Animals Area Award Back Brain Neoplasms Canis familiaris Cardiovascular system Characteristics Chronic Clinical Clinical Research Cognition Data Development Plans Disease Disease Progression Dose Drug Targeting Elements Etiology Excretory function FDA approved Failure Frontotemporal Dementia Functional disorder Future Goals Grant Guidelines Human In Vitro Intervention Investigational Drugs Investigational New Drug Application Lead Licensing Measures Mediator of activation protein Metabolism Molecular Target Morbidity - disease rate Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurologic Neuroprotective Agents No-Observed-Adverse-Effect Level Oral Oryctolagus cuniculus Pathology Patients Pharmaceutical Preparations Pharmacotherapy Phase Phase III Clinical Trials Pilot Projects Preparation Proteins Publishing Rattus Readiness Reporting Research Safety Small Business Innovation Research Grant Staining method Stains Suggestion Symptoms TNF gene Telemetry Therapeutic Thioflavin S Toxicology Transgenic Organisms Treatment Protocols absorption base clinical development cognitive function cytokine developmental toxicology drug candidate drug development efficacy study factor A good laboratory practice improved inhibitor/antagonist meetings metabolic abnormality assessment mortality mouse model neuroinflammation neuropathology novel pre-clinical preclinical study safety study safety testing small molecule symptom treatment tau phosphorylation trend tumor necrosis factor-alpha inhibitor

项目摘要

ABSTRACT The goal of this proposal is to develop tumor necrosis factor α (TNFα)-inhibiting compounds as neuroprotectant drugs for treating Alzheimer’s disease (AD). Current FDA-approved AD interventions are symptomatic treatments with limited efficacy which do not affect AD etiology or modify the course of disease progression. Thus, a critical need exists for a novel AD treatment directed towards AD pathophysiology. Recent studies implicate the neuroinflammatory cytokine TNF-α as a key mediator in AD- associated neurodegenerative pathology. Multiple preclinical and clinical studies indicate that TNFα is a “druggable” molecular target to modify the course of AD progression. Preliminary Studies demonstrate that our lead compound shows potent TNFα inhibition in vitro. Our Phase 1 SBIR studies demonstrate that our small molecule TNFα inhibitor administered orally every day for 10 months significantly improved cognitive function in the triple-transgenic (3xTg) AD mouse model. Our compound also modulated brain TNFα protein levels and halted the progress of AD-associated neuropathology including Aß plaques and neurofibrillary tangles as assessed by immunohistological staining. No morbidity, mortality or any obvious side effects were observed despite the long-term oral daily treatment regimen with our compound. Taken together, these data strongly suggest that our lead compound is an excellent anti-AD drug candidate. The proposed studies are following up on recently awarded phase 2 SBIR where we are performing several key FDA-required IND studies. The proposed CRP grant studies will build on the phase 2 SBIR studies to lead to an IND submission. Key Aims include large animal safety toxicology studies and preparation for Pre-IND meeting with the FDA.

抽象的该提案的目标是开发肿瘤坏死因子 α (TNFα) 抑制化合物目前 FDA 批准的用于治疗阿尔茨海默病 (AD) 的神经保护药物。干预措施是对症治疗，效果有限，不影响 AD 病因或因此，迫切需要一种新的 AD 治疗方法。针对 AD 病理生理学。最近的研究表明神经炎症细胞因子 TNF-α 是 AD 的关键介质相关的神经退行性病理学表明。 TNFα 是一种“可成药”的分子靶点，可以改变 AD 的进展过程。初步研究表明，我们的先导化合物在体外显示出有效的 TNFα 抑制作用。我们的 1 期 SBIR 研究表明，我们的小分子 TNFα 抑制剂连续 10 个月每天口服，显着改善三重转基因小鼠的认知功能 (3xTg) AD 小鼠模型。我们的化合物还调节大脑 TNFα 蛋白水平并停止。 AD 相关神经病理学的进展，包括 Aß 斑块和神经原纤维缠结通过免疫组织学染色评估，无发病率、死亡率或任何明显的副作用。尽管采用我们的化合物进行长期口服每日治疗方案，但仍观察到了这种情况。总之，这些数据强烈表明我们的先导化合物是一种优秀的抗 AD 药物拟议的研究是最近授予的第二阶段 SBIR 的后续研究，我们在其中进行了研究。正在开展 FDA 要求的几项关键 IND 研究。拟议的 CRP 资助研究将。以第 2 阶段 SBIR 研究为基础，提交 IND 申请，主要目标包括大型动物。安全毒理学研究以及与 FDA 举行的 Pre-IND 会议的准备。