Inhibition of retinoic acid metabolism for reversal of cognitive deficits in AD

抑制视黄酸代谢以逆转 AD 认知缺陷

• 批准号: 8648292
• 负责人: Fanny Astruc Diaz
• 金额: $ 22.5万
• 依托单位: DERMAXON, LLC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8648292
• 关键词: Adult; Adverse effects; Affect; Affinity; Alzheimer' s Disease; American; Americas; Animal Model; Binding; Brain; CYP26B1 gene; Cells; Chordata; Clinical Research; Cognitive deficits; Collaborations; Computer Simulation; Cytochrome P450; Data; Dementia; Development; Disease Progression; Docking; Dose-Limiting; Drug Kinetics; Elements; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Exhibits; Extrahepatic; Family; Goals; Human; Impaired cognition; In Vitro; Individual; Inhibitory Concentration 50; Investigational New Drug Application; Lead; Learning; Ligands; Liver; Long-Term Care; Measures; Mediating; Medicine; Memory; Memory impairment; Metabolism; Methods; Mixed Function Oxygenases; Mus; Neurodegenerative Disorders; Neuronal Plasticity; Oral Administration; Outcome; Patients; Penetration; Permeability; Pharmaceutical Preparations; Phase; Play; Population; Property; Protein Isoforms; RXR; Retinoic Acid Receptor; Role; Schedule; Series; Services; Small Business Technology Transfer Research; Structure; Symptoms; Syndrome; Testing; Therapeutic; Tissues; Transgenic Animals; Tretinoin; Vitamin A; Work; base; cost; design; improved; in vivo; inhibitor/antagonist; mouse model; next generation; novel; novel strategies; novel therapeutics; preclinical study; prevent; promoter; public health relevance; retinoic acid 4-hydroxylase; skin irritation

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressive and ultimately fatal neurodegenerative disease that affects more than five million people in the USA. Currently there is no cure for AD. Available medicines are aimed only at temporarily reducing symptoms and slowing down the progression of the disease. While many new compounds have been developed to treat AD, they have not been successful in clinical studies and consequently there is a great need for development of new therapeutic strategies. Recent data show that retinoic acid (RA) plays an important role in maintaining neuronal plasticity, and learning and memory in human or in transgenic animal model of AD, and support our hypothesis that increasing RA in the brain will improve AD patient outcomes. However, RA has poor pharmacokinetics in humans and it induces its own clearance resulting in loss of activity during long-term use. In this STTR effort, Dermaxon will use inhibition of RA clearance, instead of treatment with RA itself as a novel therapeutic strategy to treat or prevent progression of cognitive impairments associated with AD. The clearance of RA is predominantly mediated by cytochrome P450 family 26 enzymes (CYP26) of which there are three isoforms: CYP26A1, CYP26B1 and CYP26C1. While CYP26A1 appears to be the human liver RA hydroxylase, CYP26B1 is predicted to be responsible for RA metabolism in extrahepatic tissues and CYP26C1 appears to prefer 9cis-RA as a substrate. In preliminary studies, different chemotypes with a nanomolar IC50 at CYP26A1 and/or CYP26B1 have been identified. Such a novel class of compounds is expected to be highly specific for the different CYP26 isoforms, thereby avoiding side effects and non-target P450 inhibition associated with previously described CYP26 inhibitors. Dermaxon's goal is to develop the next generation of novel selective inhibitors of CYP26, to increase RA concentration in the brain, and to treat memory impairment associated with AD. Using our previously discovered lead structures, we will first generate a series of new compounds with improved CYP26 inhibition potency and selectivity. We will then evaluate their pharmacokinetic properties in mice as well as their efficacy in rescuing memory deficits in the AD mouse model PS1-APP. By the end of this Phase I STTR, Dermaxon will have identified a candidate compound that selectively targets CYP26B1 and also provide evidence that these compounds exhibit in vivo efficacy in rescuing the memory deficit in AD mouse model. In the Phase II of this STTR project we will initiate FDA discussions and complete pre-clinical studies required to file an Investigational New Drug Application (IND) to initiate clinical studies.

描述（由申请人提供）：阿尔茨海默氏病 (AD) 是一种进行性且最终致命的神经退行性疾病，影响美国超过 500 万人。目前 AD 无法治愈。现有药物的目的只是暂时减轻症状并减缓疾病的进展。尽管已经开发出许多新化合物来治疗AD，但它们在临床研究中尚未取得成功，因此非常需要开发新的治疗策略。 最近的数据表明，视黄酸 (RA) 在维持人类或 AD 转基因动物模型中的神经元可塑性、学习和记忆方面发挥着重要作用，并支持我们的假设，即增加大脑中的 RA 将改善 AD 患者的预后。然而，RA 在人体中的药代动力学较差，并且会诱导自身清除，导致长期使用时失去活性。在这项 STTR 工作中，Dermaxon 将使用抑制 RA 清除，而不是治疗 RA 本身，作为一种新的治疗策略来治疗或预防与 AD 相关的认知障碍的进展。 RA 的清除主要由细胞色素 P450 家族 26 酶 (CYP26) 介导，其中存在三种亚型：CYP26A1、CYP26B1 和 CYP26C1。虽然 CYP26A1 似乎是人肝脏 RA 羟化酶，但 CYP26B1 预计负责肝外组织中的 RA 代谢，并且 CYP26C1 似乎更喜欢 9cis-RA 作为底物。 在初步研究中，已鉴定出 CYP26A1 和/或 CYP26B1 具有纳摩尔 IC50 的不同化学型。这种新型化合物预计对不同的 CYP26 亚型具有高度特异性，从而避免与先前描述的 CYP26 抑制剂相关的副作用和非靶点 P450 抑制。 Dermaxon 的目标是开发下一代新型选择性 CYP26 抑制剂，以增加大脑中 RA 的浓度，并治疗与 AD 相关的记忆障碍。利用我们之前发现的先导结构，我们将首先生成一系列具有改进的 CYP26 抑制效力和选择性的新化合物。然后，我们将评估它们在小鼠中的药代动力学特性以及它们在 AD 小鼠模型 PS1-APP 中挽救记忆缺陷的功效。 到第一阶段 STTR 结束时，Dermaxon 将鉴定出一种选择性靶向 CYP26B1 的候选化合物，并提供证据证明这些化合物在挽救 AD 小鼠模型的记忆缺陷方面表现出体内功效。在该 STTR 项目的第二阶段，我们将启动 FDA 讨论并完成提交研究性新药申请 (IND) 所需的临床前研究，以启动临床研究。