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

• 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
• 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

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）：估计睡眠剥夺和睡眠障碍估计使美国人每年超过1000亿美元的生产力，医疗费用，病假以及财产和环境损失。睡病是一种残疾疾病，是理解其他睡眠障碍的关键。脱氧是发作性睡病的另一个主要使人衰弱的症状，估计会影响60％至90％的麻醉患者。自从发现其强大的唤醒作用以来的二十年中，莫达非尼已成为用于治疗麻醉症和其他睡眠障碍过度嗜睡的处方药。尽管有强大的唤醒效果，但莫达非尼仍无法抑制弹路。莫达非尼的这种缺点可能是由于其在去甲肾上腺素转运蛋白的活性缺乏，这是几种有效的脱氧疗法的作用部位。与莫达非尼在结构上相关的化合物，但相对于去甲肾上腺素转运蛋白抑制具有新颖的药理学特征，可能比莫达非本身具有更大的治疗值。 Acenta建立了一个诺卡因/莫达非尼杂化配体的复合库，该库充当选择性单胺转运蛋白抑制剂。这些化合物的效力因细胞膜多巴胺，去甲肾上腺素和5-羟色胺转运蛋白（DAT，NET和SERT）而有所不同。这些新型化合物中的一些是有效的特定DAT抑制剂，而其他一些新化合物则具有大致相等的效力。这些混合化合物的多种药理学概况为关于发肠炎和睡眠/尾流疾病的药理学的研究提供了强大的资源。通过这笔赠款的资助，我们打算跟进我们以以下特定目的提出的令人兴奋的初步发现，以追求新型的选择性单胺转运蛋白抑制剂，以作为过度嗜睡和麻醉症的潜在治疗剂。该研究建议的具体目的是：1。基于手头的复合库，有12个具有适当DAT的有效的跨副胺配体和净选择性概况将被重新合成。此外，还将合成这些选定化合物的顺式二肌动物体，并将研究其单胺转运蛋白抑制活性。 2。将测量表现出良好选择性的那些选定化合物的剂量反应曲线，以抑制睡眠攻击和在低封蛋白/ataxin-3（HCRT/atax）小鼠的行为和脑电图水平上的睡眠攻击和脱失。 3。将对这些化合物进行临床前的ADMET研究，以表明对AIM 2中确定的过度嗜睡和发作性衰弱的潜在治疗方法，这是对过度嗜睡的潜在治疗方法。 公共卫生相关性：Acenta Discovery开发了一个基于哌啶的Nocaine/Modafinil混合体配体的复合库，可作为选择性单胺转运蛋白抑制剂。这些杂种化合物的多种药理学概况为关于发肠炎和睡眠/尾流疾病的药理学的研究提供了有力的资源，以及过度嗜睡和发肠pro养的潜在疗法。