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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要目前，通过用处方阿片类药物替代非法阿片类药物可以缓解阿片类药物使用障碍，例如美沙酮和丁丙诺啡，虽然这可能对某些患者有效，但很少有患者。因此，新药通过非药物治疗阿片类药物使用障碍成功实现戒断。阿片类药物诱导这种耐受性和依赖性的单向方法已经迟到了。第二信使 cAMP 该信号分子增强了阿片类药物的使用。该途径可以通过增加 cAMP 来预防。磷酸二酯酶 (PDE) 对 cAMP 的分解也可减弱神经炎症。在生物学水平上，长期使用阿片类药物会抑制 PDE 并增加 cAMP。吗啡会导致大脑中的免疫细胞变得促炎，而升高的 cAMP 会诱导抗炎反应。抑制剂，PDE4 抑制剂，在治疗阿片类药物等药物滥用疾病方面已显示出前景。然而，目前的抑制剂可抑制多种神经炎症。 PDE4，包括引起严重恶心和呕吐的 PDE4D 亚型，限制了这些 PDE4B 亚型的抑制不会产生无毒干扰。因此，该提案旨在推动物质使用障碍的发展。选择性 PDE4B 系列化合物显示出显着的选择性。 PDE4B 优于 PDE4D 在体外测试时，该系列显示出有效的抗炎作用。此外，先导化合物具有令人满意的药代动力学特征和良好的活性。脑渗透性、半衰期、生物利用度等。当针对其他神经目标进行测试时，先导化合物对 2 种受体具有轻微活性，这可能会减轻药物滥用在自我给药药物滥用测试中，可以减少恶心和呕吐。在模型中，先导化合物有效地减少了药物寻求行为，就像之前的 PDE4 抑制剂一样。该提案将重点关注确认目标 1 的无毒性和有效性。测试脱靶负债，这可能是目标 2 中毒性的早期指标。将评估动物模型，并诱导恶心和呕吐以领先竞争对手。最后，目标 3 将测试阿片类药物自我给药和复发的动物模型的功效。该提案的最终目标是开发一种具有卓越治疗用途的化合物治疗阿片类药物使用障碍。