Novel Small Molecules For Acute Liver Failure

治疗急性肝衰竭的新型小分子

• 批准号: 7217009
• 负责人: PRAKASH NARAYAN
• 金额: $ 25.43万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-05 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217009
• 关键词: 3-Dimensional; Acetaminophen; Acute; Acute Liver Failure; Adult; Alcohols; Attenuated; Benchmarking; Biology; Bromodeoxyuridine; Cessation of life; Chemicals; Clinical; Clinical Trials; Condition; Data; Depth; Development; Dose; Drug Kinetics; Drug effect disorder; Enzymes; Experimental Models; Future; Genes; Goals; Growth Factor; Head; Hepatic; Hepatic Insufficiency; Hepatocyte; Hepatocyte Growth Factor; Histopathology; In Vitro; Injury; Intellectual Property; International; Kentucky; Knowledge; Laboratories; Lawyers; Lead; Legal patent; Libraries; Liver; Liver Failure; Liver Fibrosis; Liver Regeneration; Liver diseases; Medicine; Modeling; Molecular Weight; Morbidity - disease rate; Natural regeneration; Numbers; Operative Surgical Procedures; Oral; Organ; Organ Transplantation; Outcome; PCNA gene; Paper; Partial Hepatectomy; Pathway interactions; Patients; Phage Display; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Physiological; Pre-Clinical Model; Production; Protein Chemistry; Proteins; Proteolysis; Proteomics; Range; Rattus; Relative (related person); Research; Resources; Rodent Model; Safety; Scheme; Scientist; Serum; Signal Transduction; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Solutions; Specificity; Structure; Syndrome; System; Technology; Testing; Therapeutic; Therapeutic Uses; Thioacetamide; Training; Translational Research; Transplant Surgeon; Transplantation; Universities; Wisconsin; analog; cost; day; experience; improved; in vivo; liver transplantation; mimetics; molecular modeling; mortality; novel; novel therapeutics; pharmacophore; pre-clinical; programs; research study; small molecule; symposium; tool; translational study

DESCRIPTION (provided by applicant): Acute liver failure (ALF) constitutes a challenge to clinicians and scientists alike. Commonly associated with the alcohol-acetaminophen syndrome, its clinical course is unpredictable and polarizing, with death as the outcome in a large percentage of cases. Given the lack of specific therapy, organ transplantation is the only clinically effective strategy. Consequently, the field is ripe for translational studies that identify and develop new therapeutic strategies that attenuate hepatocyte death, promote hepatic regeneration and improve outcome. In a best-case scenario, such therapeutics will accelerate spontaneous regeneration of the liver and preclude the need for transplantation; in the most severe cases, they will serve as a "hepatic bridge" until transplantation. Significant evidence suggests that scatter factor / hepatocyte growth factor, exerts direct hepatoprotective effects and can potentially be used as a therapeutic in ALF. However, the feasibility of using this growth factor in the form of gene or protein therapy is compounded by numerous logistical issues. Low molecular weight compounds that mimic the activity of SF/HGF could overcome these logistical difficulties and provide effective therapy. Using a product discovery engine comprising phage display, 3-dimensional molecular modeling, protein chemistry and preclinical biology, we have identified Ang 1170, an organic small molecule SF/HGF mimetic. Our studies indicate that Ang 1170 activates the SF/HGF/c-Met pathway and exerts organoprotective effects. Importantly, in a rodent model of ALF, Ang 1170 reduces mortality, and attenuates hepatic injury. We have since constructed a structural library around Ang 1170 comprising 21 compounds with potential SF/HGF-like activity. The goal of this Phase I application is to couple targeted proteomics to in vivo efficacy studies in order to identify a lead candidate (Ang 1170 or one of its analogs) within this library for the treatment of ALF. The lead candidate emerging from this study will be submitted to in- depth, preclinical SBIR Phase II studies (oral and delayed efficacy, preclinical models of ALF combining co- morbid conditions, pharmacokinetics and safety studies) with the ultimate objective of using a small molecule SF/HGF-mimetic for therapeutic use in ALF. Acute liver failure remains a significant cause of morbidity and mortality. A small molecule hepatocyte growth factor mimetic that is hepatoprotective is of tremendous clinical benefit.

描述（由申请人提供）：急性肝衰竭（ALF）对临床医生和科学家都构成了挑战。通常与酒精-对乙酰氨基酚综合征相关，其临床过程不可预测且两极分化，大部分病例的结局是死亡。由于缺乏特异性治疗，器官移植是临床上唯一有效的策略。因此，该领域的转化研究已经成熟，可以识别和开发新的治疗策略，以减轻肝细胞死亡，促进肝再生和改善结果。在最好的情况下，这种疗法将加速肝脏的自发再生，并排除移植的需要;在最严重的情况下，它们将作为“肝桥”，直到移植。大量证据表明，分散因子/肝细胞生长因子，发挥直接的肝保护作用，并可能被用作ALF的治疗。然而，以基因或蛋白质疗法的形式使用这种生长因子的可行性由于许多后勤问题而变得复杂。模拟SF/HGF活性的低分子量化合物可以克服这些后勤困难并提供有效的治疗。利用包括噬菌体展示、三维分子建模、蛋白质化学和临床前生物学的产品发现引擎，我们已经鉴定了Ang 1170，一种有机小分子SF/HGF模拟物。我们的研究表明，Ang 1170激活SF/HGF/c-Met通路并发挥器官保护作用。重要的是，在ALF的啮齿动物模型中，Ang 1170降低死亡率，并减轻肝损伤。此后，我们构建了一个围绕Ang 1170的结构文库，其中包含21种具有潜在SF/HGF样活性的化合物。该I期申请的目标是将靶向蛋白质组学与体内功效研究相结合，以在该文库中鉴定用于治疗ALF的主要候选物（Ang 1170或其类似物之一）。本研究产生的主要候选药物将提交至深入的临床前SBIR II期研究（口服和延迟疗效、ALF临床前模型结合共病、药代动力学和安全性研究），最终目的是使用小分子SF/HGF模拟物治疗ALF。急性肝衰竭仍然是发病率和死亡率的重要原因。一种具有保肝作用的小分子肝细胞生长因子模拟物具有巨大的临床益处。