Novel inhibitor of PDE4 for the treatment of opioid use disorder

用于治疗阿片类药物使用障碍的新型 PDE4 抑制剂

• 批准号: 10157684
• 负责人: ATUL VARADHACHARY
• 金额: $ 34.99万
• 依托单位: FANNIN PARTNERS, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10157684
• 关键词: Abstinence; Affect; Animal Model; Anti-Inflammatory Agents; Attenuated; Binding; Bioavailable; Biochemical; Biological; Biological Availability; Brain; Brain region; Buprenorphine; CREB1 gene; Categories; Cell Nucleus; Cells; Cessation of life; Chemicals; Chronic; Clinic; Clinical; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Data; Dependence; Development; Disease; Distress; Dopamine Receptor; Dose; Dose-Limiting; Drug Kinetics; Effectiveness; Enzymes; Exhibits; Family member; Feedback; Genes; Genetic Transcription; Goals; Gold; Half-Life; Illicit Drugs; Immune; In Vitro; Inflammatory; Inflammatory Response; Lead; Link; Maximum Tolerated Dose; Methadone; Modeling; Morphine; Naloxone; Narcan; Nausea; Nausea and Vomiting; Neurologic; New Agents; Opioid; Opioid agonist; Oral; Outcome; Overdose; PDE4B; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phosphodiesterase Inhibitors; Plasma; Property; Rattus; Recurrence; Relapse; Rolipram; Safety; Self Administration; Series; Shrews; Signal Transduction; Signaling Molecule; Small Business Innovation Research Grant; Specificity; Substance Use Disorder; Substance abuse problem; Synaptic Transmission; Testing; Therapeutic; Therapeutic Uses; Toxic effect; Toxicology; Vomiting; Withdrawal; Work; activating transcription factor; addiction; adherence rate; androgenic; clinical candidate; clinical development; craving; dosage; drug seeking behavior; effective therapy; efficacy testing; gastrointestinal; high throughput screening; illicit opioid; in vitro Assay; in vitro testing; in vivo; in vivo Model; inhibitor/antagonist; lead series; neurobehavioral; neuroinflammation; non-opioid analgesic; novel; opiate tolerance; opioid overdose; opioid use; opioid use disorder; opioid withdrawal; phosphodiesterase IV; phosphoric diester hydrolase; pre-clinical; preclinical development; prescription opioid; prevent; receptor; scale up; targeted agent

Project Summary Currently, opioid-use disorders are mitigated by replacing illicit opioids with prescription opioids, like methadone and buprenorphine. While this may work for some patients, few patients successfully reach opioid-abstinence. Thus, new agents targeting opioid-use disorders via non- opioid approaches are overdue. One-way opioids induce such tolerance and dependence is through a secondary messenger, cAMP. This signaling molecule reinforces the use of opioids on a biochemical level. This pathway can be altered by an increase of cAMP, by preventing the breakdown of cAMP by phosphodiesterases, PDE. Neuroinflammation is also attenuated by the inhibition of PDE and increased cAMP. On a biological level, chronic opioid-use causes neuroinflammation. Morphine causes immune cells in the brain to become pro-inflammatory, while elevated cAMP induces an anti-inflammatory response. Previous phosphodiesterase-4 inhibitors, PDE4 inhibitors, have shown promise in treating substance abuse disorders, like opioid- use disorders, by reducing this neuroinflammation. However, current inhibitors inhibit multiple PDE4s, including the PDE4D subtype that induces significant nausea and vomiting, limiting these inhibitors’ therapeutic utility. Inhibition of the PDE4B subtype non-toxically interferes with the classic feedback loop in substance use disorders. Thus, this proposal aims to advance a lead compound from a selective PDE4B series. The lead compound has shown significant selectivity for PDE4B over PDE4D. When tested in vitro, the series showed potent anti-inflammatory activity. Additionally, the lead compound has a satisfactory pharmacokinetic profile with decent brain penetration, half-life, bioavailability, etc. When tested against other neurological targets, the lead compound had slight activity against 2 receptors, which may mitigate substance abuse disorders and reduce nausea and vomiting. When tested in a self-administration substance abuse model, the lead compound potently reduced the drug seeking behavior, like prior PDE4 inhibitors. This proposal will focus on confirming lack of toxicity and efficacy. For aim 1, the lead will be tested for off-target liabilities, which may be early indicators of toxicities. In aim 2, toxicity within animal models will be assessed, and induction of nausea and vomiting to the leading competitor. Finally, aim 3 will test efficacy in animal models of opioid self-administration and recurrence. The ultimate goal of this proposal will advance a compound with superior therapeutic use for the treatment of opioid-use disorders.

项目摘要 目前，通过用处方opioids代替非法的opioids，可以减轻OPioID-使用疾病， 像Metagadone和丁丙诺啡一样。虽然这可能对某些患者有用，但很少有患者 成功达到阿片类药物的侵犯。那是针对阿片类药物使用疾病的新特工 阿片类药物的方法逾期。单向阿片类药物诱导这种耐受性和依赖性是通过 次要信使，营地。该信号分子加强了阿片类药物在A上的使用 生化水平。通过增加营地的增加，可以改变该途径 磷酸二酯酶对cAMP的崩溃，PDE。神经炎症也被 抑制PDE并增加营地。在生物学层面，慢性阿片类药物的原因 神经炎症。吗啡会导致大脑中的免疫球成为促炎性的， 而高高的营地会影响抗炎反应。先前的磷酸二酯酶4 PDE4抑制剂抑制剂在治疗药物滥用障碍方面表现出希望，例如阿片类药物 通过减少这种神经炎症来使用疾病。但是，当前的抑制剂抑制了多个 PDE4，包括影响严重恶心和呕吐的PDE4D亚型，限制了这些 抑制剂的治疗效用。 PDE4B亚型的抑制在非毒性上干扰 物质使用障碍中的经典反馈回路。这是该提议旨在提高领先地位 选择性PDE4B系列的化合物。铅化合物已显示出明显的选择性 对于PDE4D，PDE4B。当在体外测试时，该系列显示出有效的抗炎 活动。此外，铅化合物具有满意的工厂药代动力学特征，并且不错 脑穿透，半衰期，生物利用度等。当针对其他神经系统靶标测试时 铅化合物对2种受体有轻微的活性，这可能减轻药物滥用 疾病并减少恶心和呕吐。在自我管理药物滥用中进行测试 模型，铅化合物可能会降低寻求药物的行为，例如先前的PDE4抑制剂。 该提案将着重于确认缺乏毒性和效率。对于目标1，领先将是 测试了脱靶负债，这可能是毒性的早期指标。在AIM 2中，毒性内部 将评估动物模型，并将恶心和呕吐归因于领先的竞争者。 最后，AIM 3将测试阿片类动物自我给药和复发的动物模型中的效率。这 该提案的最终目标将通过出色的疗法使用来推进化合物 治疗阿片类药物疾病。