20-HETE Formation Inhibitors in Cardiac Arrest

项目摘要 有证据表明，20-羟基二十碳四烯酸（20-HETE）是微血管的关键， 收缩调节剂，由细胞色素P450 4氧化花生四烯酸（AA）形成 CYP 4家族。我们和其他人已经在临床前证明，抑制20-HETE的形成是有效的。 在儿童和成人脑损伤的中风和心脏骤停（CA）大鼠模型中的神经保护。虽然可能性不大 在临床背景下，我们已经证明蛛网膜下腔出血脑脊液中的20-HETE水平 (SAH)患者死亡率增加>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形成在治疗神经血管损伤后脑灌注不足方面具有很大的前景。 脑损伤尽管20-HETE形成（CYP 4）抑制剂有望成为神经保护剂，但目前还没有 这类抑制剂可用于临床。少数20-HETE形成（CYP 4）抑制剂已被发现。 在文献中有报道。然而，不幸的是，所公开的所有化合物都具有阻碍其应用的缺点。 成功进入临床。通过合理的药物设计和计算方法， 确定了一个铅系列，以UPMP 00010支架为例。该系列化合物具有优异的 适用于CNS作用剂的效力和理化性质。来自该系列的化合物还 具有良好的溶解性、高的血脑屏障（BBB）渗透潜力，重要的是， 与领先的文献抑制剂相比具有稳定性。在拟议的工作中，我们的目标是进一步优化 UPMP 00010支架和我们先进的先导化合物UPMP 00022，以鉴定待测的临床前先导化合物 在脑损伤的儿科（PND 17）窒息CA大鼠模型中进行体内神经保护。我们提出了一个多- 维度优化方法来鉴定可能具有临床潜力的临床前CYP 4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、体外试验和决策算法/工作流程，以识别临床前线索， 具有适用于体内检测的特性（效价、选择性、理化性质）。在R21 我们将在体内评估我们两种最好的临床前先导药物的药代动力学和靶向参与， 为了选择最好的临床前领导人进行严格的疗效研究，将在R33期间进行 拟议工作的阶段。在R33阶段，我们将严格评估脑血流量（CBF）、神经元 退化和神经学结果以评估功效。

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.