Peripherally-restricted non-addictive cannabinoids for cancer pain treatment

口腔癌疼痛使人虚弱，也是一个重大的临床挑战，部分原因是即使是目前可用的最有效的治疗方法也受到副作用的限制。虽然化疗和放射治疗延长了生存时间，但慢性癌痛却造成了较差的生活质量。除了呼吸道、胃肠道和中枢神经系统(CNS)的副作用外，阿片类止痛药的标准护理长期疗效有限，原因是出现耐受性、依赖性和阿片类药物诱导的痛敏，随之而来的剂量增加往往导致处方阿片类药物的滥用。因此，对癌症疼痛的更有效治疗的需求显然尚未得到满足，这些治疗将具有良好的治疗/副作用概况比率，特别是缺乏目前临床阿片类药物的中枢神经系统副作用和滥用潜力。我们已经开发出合成的外周限制性大麻素(PRCB)止痛药，为慢性疼痛的治疗提供了一种替代方法。这些化合物以CB1受体为靶点，它们不会越过血脑屏障，我们已经在几个癌症和化疗诱导的慢性疼痛的临床前模型中证明了它们的有效性，所有这些都实际上缺乏中枢神经系统介导的副作用和耐受性发展。在这里，我们提出了一项里程碑式的进展计划，包括基于SAR信息的支架合成、体外/体内筛选和IND使能研究，以开发用于癌症疼痛治疗的优化的PRCB。特定目标(SA)1使用迭代合成方法和高通量体外筛选来评估靶标活性、外周选择性和代谢稳定性，以发现具有优化药物特性的新的PRCB类似物。SA2利用行业标准的体外分析来评估溶解性、蛋白质结合、潜在的细胞毒性、肝酶诱导和脱靶活性，以进一步为PRCB的优化提供信息。SA3介绍了最有前景的PRCB的体内口腔癌疼痛抑制、中枢神经系统副作用、药代动力学、药效学靶点参与生物标记物、成瘾易感性、毒理学和安全药理学。从这些研究中脱颖而出的最佳候选者将在SA4中晋级，由NIH CRO进行全面扩大和IND使能研究，然后是IND申请和批准。这些研究是进行第一人、单组、双盲、安慰剂对照的口腔癌疼痛最佳PRCB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.