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。目前还没有治愈阿尔茨海默病的方法。现有药物的目的只是暂时减轻症状和减缓疾病的进展。虽然已经开发出许多治疗阿尔茨海默病的新化合物，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。最近的数据显示，维甲酸（RA）在维持阿尔茨海默病人类或转基因动物模型的神经元可塑性和学习记忆中发挥重要作用，并支持我们的假设，即增加大脑中RA的含量将改善阿尔茨海默病患者的预后。然而，类风湿性关节炎在人体内的药代动力学很差，在长期使用过程中会诱导自身清除，导致活性丧失。在这项STTR研究中，Dermaxon将利用抑制类风湿性关节炎的清除，而不是用类风湿性关节炎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，其中有三种亚型：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RA代谢，CYP26C1似乎更倾向于9cis-RA作为底物。在初步研究中，已经确定了CYP26A1和/或CYP26B1具有纳摩尔IC50的不同化学型。这类新型化合物有望对不同的CYP26亚型具有高度特异性，从而避免了与先前描述的CYP26抑制剂相关的副作用和非靶标P450抑制。Dermaxon的目标是开发下一代CYP26的新型选择性抑制剂，以增加RA在大脑中的浓度，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，我们将首先产生一系列具有提高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体内的药代动力学特性，以及它们在AD小鼠模型PS1-APP中修复记忆缺陷的功效。在I期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小鼠模型中的记忆缺陷方面表现出体内功效。在这个STTR项目的第二阶段，我们将启动FDA讨论并完成临床前研究，以提交新药研究申请（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.