Peripherally-restricted non-addictive cannabinoids for cancer pain treatment

口腔癌疼痛使人衰弱，是一个重大的临床挑战，部分原因是即使是目前最有效的补救措施也受到副作用的限制。虽然化疗和放疗可以延长生存期，但慢性癌症疼痛会导致生活质量下降。除了其呼吸系统、胃肠道和中枢神经系统（CNS）副作用外，标准治疗阿片类镇痛剂的长期有效性有限，原因是耐受性、依赖性和阿片类诱导的痛觉过敏的发展，随后的剂量递增通常导致处方阿片类药物滥用。因此，对于更有效的癌症疼痛治疗存在明显未满足的需求，所述治疗将具有有利的治疗/副作用特征比，特别是缺乏当前临床阿片类药物的CNS副作用和滥用潜力。我们开发了合成外周限制性大麻素（PRCB）镇痛药，为治疗慢性疼痛提供了另一种方法。这些化合物靶向CB 1受体，它们不会穿过血脑屏障，并且我们已经在癌症和化疗诱导的慢性疼痛的几种临床前模型中证明了它们的有效性，所有这些都几乎没有CNS介导的副作用和耐受性发展。在这里，我们提出了一个里程碑驱动的进展计划SAR知情的支架为基础的合成，在体外/体内筛选，和IND使研究开发一个优化的PRCB癌症疼痛治疗。Specific Aim（SA）1使用迭代合成方法以及高通量体外筛选，评估靶活性，外周选择性和代谢稳定性，以发现具有优化药物特性的新PRCB类似物。SA 2利用行业标准体外试验评估溶解度、蛋白结合、潜在细胞毒性、肝酶诱导和脱靶活性，以进一步为PRCB优化提供信息。SA 3描述了最有前途的PRCB的体内口腔癌疼痛抑制、CNS副作用、药代动力学、药效学靶点结合生物标志物、成瘾倾向、毒理学和安全药理学。从这些研究中产生的最佳候选药物将在SA 4中由NIH CRO进行全面扩大和IND使能研究，然后进行IND申请和批准。这些研究是进行口腔癌疼痛最佳PRCB的首次人体I期、单组、双盲、安慰剂对照、剂量递增试验的先决条件，以确定其安全性、PK、PD和剂量效应，并确认靶点参与。

Oral cancer pain is debilitating and a significant clinical challenge, in part because even the most efficacious of the currently available remedies are limited by side effects. While chemotherapy and radiotherapy prolong survival, chronic cancer pain creates a poor quality of life. In addition to their respiratory, gastrointestinal and central nervous system (CNS) side effects, the standard of care opioid analgesics have limited long-term effectiveness, due to development of tolerance, dependence, and opioid-induced hyperalgesia, with consequent dose escalations often leading to abuse of prescription opioids. Thus, there is a clear unmet need for more efficacious treatments for cancer pain that will possess favorable therapeutic/side effect profile ratios and in particular lack the CNS side effects and the abuse potential of current clinical opioid medications. We have developed synthetic peripherally-restricted cannabinoid (PRCB) analgesics that offer an alternative approach to the treatment of chronic pain. These compounds target the CB1 receptor, they don't cross the blood-brain barrier, and we have already demonstrated their effectiveness in several pre-clinical models of cancer- and chemotherapy-induced chronic pain, all with a virtual lack of CNS-mediated side effects and tolerance development. Here we propose a milestone-driven progression plan of SAR-informed scaffold-based synthesis, in vitro/in vivo screening, and IND enabling studies for the development of an optimized PRCB for cancer pain treatment. Specific Aim (SA) 1 uses an iterative synthetic approach together with high-throughput in vitro screens that assess target activity, peripheral selectivity, and metabolic stability to discover new PRCB analogs with optimized drug properties. SA2 utilizes industry-standard in vitro assays to assess solubility, protein binding, potential cell toxicity, hepatic enzyme induction, and off-target activity to further inform PRCB optimization. SA3 profiles the in vivo oral cancer pain suppression, CNS side effects, pharmacokinetics, pharmacodynamic target engagement biomarkers, addiction liability, toxicology, and safety pharmacology of the most promising PRCBs. The best candidate to emerge from these studies will then advance in SA4 to full scale-up and IND-enabling studies by NIH CROs, followed by IND application and approval. These studies are prerequisite to the conduct of first-in-man Phase I, single group, double-blind, placebo-controlled, dose-escalation trial of optimal PRCB for oral cancer pain in order to determine its safety, PK, PD and dose-effect, and to confirm target engagement.