Piperidine-Based Compounds as Therapeutics for Narcolepsy-Cataplexy

哌啶基化合物作为发作性睡病-猝倒症的治疗药物

基本信息

批准号：
7270708
负责人：
Jia Zhou
金额：
$ 3.8万
依托单位：
ACENTA DISCOVERY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-09 至 2007-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7270708
关键词：
Affect American Arizona Arts Behavioral Biological Assay Cataplexy Cell membrane Chemistry Clinical assessments Collaborations Data Development Disadvantaged Disease Dopamine Dose Drug Kinetics Drug Prescriptions Ensure Equipment Exhibits Funding Grant Hand Housing Hybrids International Laboratories Laboratory Research Legal patent Libraries Licensing Ligands MJD1 protein Measures Medical Modafinil Molecular Neurobiology Mus Narcolepsy Norepinephrine Organic Chemistry Patients Pharmaceutical Chemistry Pharmacology Pharmacology and Toxicology Productivity Property Public Health Research Research Personnel Research Proposals Resources Safety Science Screening procedure Senior Scientist Series Sick Leave Site Sleep Sleep Deprivation Sleep Disorders Symptoms Technology Texas Therapeutic Toxicology Universities base cost design experience follow-up hypocretin inhibitor/antagonist methyl 4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate monoamine noradrenaline transporter novel piperidine pre-clinical response scale up serotonin transporter stem

项目摘要

DESCRIPTION (provided by applicant): Sleep deprivation and sleep disorders are estimated to cost Americans over $100 billion annually in lost productivity, medical expenses, sick leave, and property and environmental damage. Narcolepsy is a disabling illness and a key to understanding other sleep disorders. Cataplexy is another major debilitating symptom of narcolepsy, and is estimated to affect 60 to 90% of narcoleptic patients. In the two decades since the discovery of its robust wake-promoting effect, modafinil has become the most widely used prescription drug for treatment of excessive sleepiness in narcolepsy and other sleep disorders. Its robust wake-promoting effect notwithstanding, modafinil fails to suppress cataplexy. This disadvantage of modafinil likely stems from its lack of activity at the norepinephrine transporter, the site of action for several potent cataplexy therapeutics. Compounds that are structurally related to modafinil, but exhibit novel pharmacological profiles with respect to norepinephrine transporter inhibition, may be of greater therapeutic value than modafinil itself. Acenta has established a compound library of nocaine/modafinil hybrid ligands that act as selective monoamine transporter inhibitors. The compounds vary in their potency as inhibitors of the cell membrane dopamine, norepinephrine and serotonin transporters (DAT, NET and SERT). Some of these novel compounds are potent, specific DAT inhibitors, while some others inhibit both DAT and NET with roughly equal potency. The diverse pharmacological profiles of these hybrid compounds provide a powerful resource for studies on the pharmacology of narcolepsy and of sleep/wake disorders in general. Through funding from this grant, we intend to follow-up on the exciting preliminary findings we have made with the following specific aims in pursuit of novel selective monoamine transporter inhibitors as potential therapeutics for excessive sleepiness and narcolepsy-cataplexy. The specific aims of this research proposal are: 1. Based on the compound library in hand, 12 potent trans-piperidine ligands possessing appropriate DAT and NET selectivity profiles will be resynthesized. Additionally, the cis-diastereomers of these selected compounds will also be synthesized and their monoamine transporter inhibitory activity will be investigated. 2. The dose-response curves of those selected compounds that exhibit good selectivity will be measured for the suppression of sleep attacks and cataplexy at the behavioral and electroencephalographic levels in hypocretin/ataxin-3 (hcrt/atax) mice. 3. Pre-clinical ADMET studies will be carried out on those compounds showing the greatest promise as potential therapeutics for excessive sleepiness and narcolepsy-cataplexy as determined in Aim 2. Public Health Relevance: Acenta Discovery has developed a compound library of piperidine-based nocaine/modafinil hybrid ligands that act as selective monoamine transporter inhibitors. The diverse pharmacological profiles of these hybrid compounds provide a powerful resource for studies on the pharmacology of narcolepsy and of sleep/wake disorders in general and the potential therapeutics for excessive sleepiness and narcolepsy-cataplexy.

描述（由申请人提供）：据估计，睡眠不足和睡眠障碍每年给美国人造成超过 1000 亿美元的损失，包括生产力损失、医疗费用、病假以及财产和环境损害。发作性睡病是一种致残性疾病，也是了解其他睡眠障碍的关键。猝倒是发作性睡病的另一个主要衰弱症状，估计影响 60% 至 90% 的发作性睡病患者。自发现其强大的促醒作用以来的二十年里，莫达非尼已成为治疗发作性睡病和其他睡眠障碍中过度嗜睡的最广泛使用的处方药。尽管莫达非尼具有强大的促醒作用，但它无法抑制猝倒。莫达非尼的这一缺点可能源于其去甲肾上腺素转运蛋白缺乏活性，而去甲肾上腺素转运蛋白是几种有效的猝倒疗法的作用部位。结构上与莫达非尼相关但在去甲肾上腺素转运蛋白抑制方面表现出新颖的药理学特征的化合物可能比莫达非尼本身具有更大的治疗价值。 Acenta 建立了诺卡因/莫达非尼混合配体的化合物库，可作为选择性单胺转运蛋白抑制剂。这些化合物作为细胞膜多巴胺、去甲肾上腺素和血清素转运蛋白（DAT、NET 和 SERT）抑制剂的效力各不相同。其中一些新型化合物是有效的、特异性的 DAT 抑制剂，而另一些化合物则以大致相同的效力抑制 DAT 和 NET。这些混合化合物的不同药理学特征为研究发作性睡病和一般睡眠/觉醒障碍的药理学提供了强大的资源。通过这笔赠款的资助，我们打算对我们取得的令人兴奋的初步发现进行后续研究，具体目标如下，以寻求新型选择性单胺转运蛋白抑制剂作为过度嗜睡和发作性睡病猝倒的潜在治疗方法。本研究计划的具体目标是： 1. 基于现有的化合物库，将重新合成12种具有适当DAT和NET选择性特征的有效反式哌啶配体。此外，还将合成这些选定化合物的顺式非对映体，并研究它们的单胺转运蛋白抑制活性。 2.将在下丘脑分泌素/ataxin-3(hcrt/atax)小鼠的行为和脑电图水平上测量表现出良好选择性的那些所选化合物的剂量反应曲线，以抑制睡眠发作和猝倒。 3. 临床前 ADMET 研究将针对目标 2 中确定的那些最有希望作为过度嗜睡和发作性睡病猝倒症潜在治疗药物的化合物进行。公共卫生相关性：Acenta Discovery 开发了基于哌啶的诺卡因/莫达非尼混合配体的化合物库，可作为选择性单胺转运蛋白抑制剂。这些混合化合物的不同药理学特征为研究发作性睡病和一般睡眠/觉醒障碍的药理学以及过度嗜睡和发作性睡病猝倒的潜在治疗方法提供了强大的资源。