20-HETE Formation Inhibitors in Cardiac Arrest

20-HETE 形成抑制剂在心脏骤停中的作用

• 批准号: 10298788
• 负责人: Donna M Huryn
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10298788
• 关键词: ABCB1 gene; Acute; Adult; Animal Model; Arachidonic Acids; Biological Assay; Blood; Blood - brain barrier anatomy; Brain; Brain Injuries; Brain hemorrhage; CYP1A2 gene; Cerebrospinal Fluid; Cerebrovascular Circulation; Characteristics; Childhood; Clinic; Clinical; Cognitive; Computer Models; Computing Methodologies; Critical Care; Cytochrome P450; Data; Dose; Drug Design; Drug Kinetics; Emergency Medicine; Ensure; Family; Female; Goals; Heart Arrest; Homology Modeling; Human; Hydroxyeicosatetraenoic Acids; Impairment; In Vitro; Injury; Intervention; Intravenous; Kinetics; Lead; Literature; Liver; Liver Microsomes; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Motor; Nerve Degeneration; Neurological outcome; Neurons; Neuroprotective Agents; Outcome; Parents; Patients; Pediatric Brain Injury; Pharmaceutical Chemistry; Pharmacology; Phase; Plasma; Property; Protein Isoforms; Rattus; Recommendation; Recovery; Reporting; Series; Solubility; Stroke; Subarachnoid Hemorrhage; System; Work; base; blood-brain barrier penetration; blood-brain barrier permeabilization; cheminformatics; clinically relevant; clinically translatable; computational chemistry; constriction; decision making algorithm; design; efficacy evaluation; efficacy study; experimental study; hypoperfusion; in vitro Assay; in vivo; in vivo evaluation; inhibitor/antagonist; lead dose; lead series; lipidomics; male; mortality; multidisciplinary; natural hypothermia; neuroprotection; neurovascular; novel; novel strategies; oxidation; postnatal; pre-clinical; scaffold; stroke event; thromboembolic stroke

Project Summary Evidence has demonstrated that 20-hydroxyeicosatetraenoic acid (20-HETE) is a key microvascular constrictive regulator and is formed by the omega-oxidation of arachidonic acid (AA) by the cytochrome P450 4 (CYP4) family. We and others have pre-clinically demonstrated that inhibition of 20-HETE formation is neuroprotective in both stroke and the cardiac arrest (CA) rat models of pediatric and adult brain injury. Also, in the clinical setting, we have shown that 20-HETE levels in the cerebrospinal fluid of subarachnoid hemorrhage (SAH) patients are associated with a >3-fold increase in mortality and a >2-fold increase in poor outcomes post-insult. All available preclinical and clinical evidence suggest that acute interventions that aim to inhibit 20- HETE formation hold great promise in the treatment of post-injury brain hypoperfusion after neurovascular brain injury. Despite the promise a 20-HETE formation (CYP4) inhibitor holds as a neurpotectant, there is no such inhibitor available for clinical use. A small number of the 20-HETE formation (CYP4) inhibitors have been reported in the literature. Unfortunately however, all compounds disclosed have shortcomings that impede their successful advancement to the clinic. Through rational drug design and computational methods we have identified a lead series, exemplified by the UPMP00010 scaffold. Compounds from this series have excellent potency and physicochemical properties appropriate for CNS-acting agents. Compounds from this series also have good solubility, high blood brain barrier (BBB) permeability potential and importantly, high metabolic stability when compared to leading literature inhibitors. In the proposed work, we aim to optimize further the UPMP00010 scaffold, and our advanced lead UPMP00022, to identify preclinical lead compounds to be tested in vivo for neuroprotection in the pediatric (PND17) asphyxial CA rat model of brain injury. We propose a multi- dimensional optimization approach to identify preclinical CYP4 inhibitors that may have clinical potential. In the R21 phase of the proposed work, we will harness rational drug design, computational and medicinal chemistry, cheminformatics, in vitro assays and a decision making algorithm/workflow to identify preclinical leads that have suitable characteristics (potency, selectivity, physicochemical properties) for testing in vivo. In the R21 phase we will evaluate our two best preclinical leads in vivo for pharmacokinetics and target engagement in order to select the best preclinical lead for a rigorous efficacy study that will be conducted during the R33 phase of the proposed work. In the R33 phase, we will rigorously evaluate cerebral blood flow (CBF), neuronal degeneration and neurological outcomes for assessing efficacy.

项目摘要 有证据表明，20-羟基二十碳四烯酸(20-HETE)是一种重要的微血管物质。 收缩调节因子，由细胞色素P450 4对花生四烯酸(AA)的omega氧化形成 (CYP4)家族。我们和其他人已经在临床前证明，抑制20-HETE的形成是 在中风和心跳骤停(CA)儿童和成人脑损伤大鼠模型中的神经保护。此外，在 在临床背景下，我们已经发现蛛网膜下腔出血患者脑脊液中20-HETE水平 (SAH)患者的死亡率增加3倍，不良结局增加2倍 侮辱后。所有可用的临床前和临床证据表明，旨在抑制20- HETE的形成在治疗神经血管损伤后脑低灌注方面具有很大的前景 脑部受伤。尽管20-HETE形成(CyP4)抑制剂被认为是神经保护剂，但没有 这种抑制剂可供临床使用。少量的20-HETE形成(CYP4)抑制剂已经被 在文献中有报道。然而，不幸的是，所有披露的化合物都有缺陷，阻碍了它们的 成功地进入了临床。通过合理的药物设计和计算方法，我们拥有 确定了以UPMP00010脚手架为例的铅系列。这一系列的化合物具有极好的 适合于CNS作用剂的效力和物理化学性质。这一系列的化合物也 具有良好的溶解性，高血脑屏障(BBB)渗透潜力，更重要的是，高代谢率 与领先的文献抑制剂相比时的稳定性。在拟议的工作中，我们的目标是进一步优化 UPMP00010支架，以及我们先进的先导UPMP00022，以识别待测试的临床前先导化合物 在体脑保护对儿童(PND17)窒息CA大鼠脑损伤模型的影响。我们提出了一个多- 维度优化方法，以确定可能具有临床潜力的临床前细胞色素P4抑制剂。在 R21阶段的拟议工作，我们将利用合理的药物设计、计算和药物化学， 化学信息学、体外分析和决策算法/工作流程，以确定临床前线索 具有适合体内测试的特性(效价、选择性、物理化学性质)。在R21 阶段我们将在体内评估我们最好的两个临床前线索的药代动力学和靶向参与 为将在R33期间进行的严格疗效研究选择最佳临床前导联 拟议工作的阶段。在R33期，我们将严格评估脑血流量(CBF)、神经元 用于评估疗效的变性和神经学结果。