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

描述（由申请人提供）：阿尔茨海默病（AD）是一种进行性和最终致命的神经退行性疾病，在美国影响超过500万人。目前还没有治愈AD的方法。现有药物的目的只是暂时减轻症状和减缓疾病的进展。虽然已经开发了许多新的化合物来治疗AD，但它们在临床研究中并不成功，因此非常需要开发新的治疗策略。 近年来的研究表明，视黄酸（RA）在维持神经元的可塑性、学习记忆以及人类和AD转基因动物模型中起重要作用，这支持了我们的假设，即增加脑中RA的含量将改善AD患者的预后。然而，RA在人体中的药代动力学较差，并且它诱导其自身清除，导致在长期使用期间活性丧失。在这项STTR研究中，Dermaxon将使用抑制RA清除而不是RA本身治疗作为治疗或预防AD相关认知障碍进展的新型治疗策略。RA的清除主要由细胞色素P450家族26酶（CYP 26）介导，其中有三种亚型：CYP 26 A1、CYP 26 B1和CYP 26 C1。虽然CYP 26 A1似乎是人肝脏RA羟化酶，但预计CYP 26 B1负责肝外组织中的RA代谢，CYP 26 C1似乎更喜欢9 cis-RA作为底物。 在初步研究中，已经鉴定了在CYP 26 A1和/或CYP 26 B1上具有纳摩尔IC 50的不同化学型。预期此类新型化合物对不同的CYP 26同种型具有高度特异性，从而避免与先前描述的CYP 26抑制剂相关的副作用和非靶向P450抑制。Dermaxon的目标是开发下一代新型CYP 26选择性抑制剂，以增加大脑中的RA浓度，并治疗与AD相关的记忆障碍。使用我们先前发现的先导结构，我们将首先产生一系列具有改善的CYP 26抑制效力和选择性的新化合物。然后，我们将评估其在小鼠中的药代动力学特性以及其在AD小鼠模型PS1-APP中挽救记忆缺陷的疗效。在本I期STTR结束时，Dermaxon将确定一种选择性靶向CYP 26 B1的候选化合物，并提供证据证明这些化合物在挽救AD小鼠模型记忆缺陷方面表现出体内疗效。在该STTR项目的第二阶段，我们将启动FDA讨论并完成临床前研究，以便提交新药临床试验申请（IND）以启动临床研究。

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.