Novel inhibitor of PDE4 for the treatment of opioid use disorder

项目摘要 目前，通过用处方类阿片替代非法类阿片， 比如美沙酮和丁丙诺啡虽然这可能对一些患者有效，但很少有患者 成功实现阿片类药物戒断。因此，新的药物靶向阿片类药物使用障碍，通过非 阿片类药物方法早该采用了。单向阿片类药物诱导这种耐受性和依赖性是通过 第二信使cAMP这种信号分子加强了阿片类药物在 生化水平。这一途径可以通过增加cAMP，通过阻止 磷酸二酯酶（PDE）分解cAMP。神经炎症也被 PDE抑制和cAMP增加。在生物学层面上，长期使用阿片类药物会导致 神经炎症吗啡导致大脑中的免疫细胞变得促炎， 而升高的cAMP诱导抗炎反应。既往磷酸二酯酶-4 抑制剂，PDE 4抑制剂，已经显示出治疗物质滥用障碍的希望，如阿片类药物- 通过减少这种神经炎症。然而，目前的抑制剂抑制多种 PDE 4，包括PDE 4D亚型，可诱导显著的恶心和呕吐，限制这些 抑制剂的治疗效用。PDE 4 B亚型的抑制非毒性地干扰 物质使用障碍的典型反馈回路因此，该提案旨在推动一项领先的 选择性PDE 4 B系列的化合物。先导化合物显示出显著的选择性 在PDE 4D上的PDE 4 B。当在体外测试时，该系列显示出有效的抗炎作用， 活动此外，先导化合物具有令人满意的药代动力学特征， 脑渗透、半衰期、生物利用度等。当针对其他神经靶点进行测试时， 先导化合物对2种受体有轻微活性，这可能会减轻药物滥用 并减少恶心和呕吐。在自我管理药物滥用测试中， 在模型中，先导化合物有效地减少了药物寻求行为，就像先前的PDE 4抑制剂一样。 该提案将重点确认缺乏毒性和有效性。对于目标1，领先将是 测试脱靶负债，这可能是毒性的早期指标。在目标2中，毒性在 将评估动物模型，并诱导恶心和呕吐的领先竞争对手。 最后，目标3将在阿片类药物自我给药和复发的动物模型中测试疗效。的 本发明的最终目标是开发一种具有上级治疗用途的化合物， 阿片类药物使用障碍的治疗。

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.