Peripherally-restricted non-addictive cannabinoids for cancer pain treatment

用于癌症疼痛治疗的外周限制性非成瘾大麻素

• 批准号: 10726405
• 负责人: CATHERINE M CAHILL
• 金额: $ 317.43万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10726405
• 关键词: Abdomen; Acute; Admission activity; Adverse effects; Agonist; Analgesic Overuse Headaches; Analgesics; Animals; Behavior; Binding Proteins; Biological Assay; Biological Markers; Brain; CNR1 gene; Cancer Model; Cannabinoids; Cardiovascular system; Catalepsy; Cells; Central Nervous System; Cerebrospinal Fluid; Chemotherapy and/or radiation; Chronic; Chronic Cancer Pain; Clinical; Clinical Trials; Consultations; Cytochrome P450; Data; Dependence; Development; Devices; Dose; Double-Blind Method; Drug Kinetics; Effectiveness; Enzyme Induction; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Hepatic; Human; Hyperalgesia; Implant; In Vitro; Indenes; Individual; Industry; Industry Standard; International; Intravenous; Investigational Drugs; Investigational New Drug Application; Lead; Legal patent; Libraries; Liver; MDCK cell; Malignant Neoplasms; Measures; Mediating; Metabolic; Migraine; Modeling; Modification; Motor; Neuropathy; New Drug Approvals; Opioid; Opioid Analgesics; Pain; Pain Measurement; Pain intensity; Pain management; Patients; Performance; Peripheral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacology Study; Phase; Placebo Control; Plasma; Plasma Proteins; Positron-Emission Tomography; Pre-Clinical Model; Prevalence; Property; Proteins; Quality of life; Radio; Receptor Activation; Research Design; Research Institute; Risk; Rodent; Safety; Sampling; Seasons; Self Administration; Site-Directed Mutagenesis; Solubility; Telemetry; Testing; Therapeutic; Tissues; Toxic effect; Toxicology; Traumatic Nerve Injury; United States National Institutes of Health; abuse liability; addiction; addiction liability; analog; awake; blood-brain barrier crossing; blood-brain barrier permeabilization; cancer pain; cancer therapy; carcinogenesis; chemical synthesis; chemotherapy; chronic pain; chronic pain management; cytotoxicity; design; drug development; drug induced liver injury; efficacious treatment; efficacy validation; experience; first-in-human; gastrointestinal; improved; in vitro Assay; in vivo; liquid chromatography mass spectrometry; malignant mouth neoplasm; member; morpholine; natural hypothermia; novel drug class; pain symptom; pharmacologic; prescription opioid; prescription opioid abuse; prototype; respiratory; scaffold; scale up; screening; side effect; standard of care; virtual

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.

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可用的最有效的补救措施也受到副作用的限制。虽然化疗和放疗延长了生存期，但慢性癌症疼痛造成生活质量低下。除了对呼吸、胃肠道和中枢神经系统（CNS）的副作用外，标准护理阿片类镇痛药的长期有效性有限，这是由于耐受性、依赖性和阿片类药物引起的痛觉过敏的发展，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，对于具有良好的治疗/副作用比例，特别是缺乏中枢神经系统副作用和当前临床阿片类药物滥用潜力的更有效的癌症疼痛治疗方法，显然存在未满足的需求。我们已经开发了合成外周限制性大麻素（PRCB）镇痛药，为慢性疼痛的治疗提供了另一种方法。这些化合物以CB1受体为靶点，它们不会穿过血脑屏障，我们已经在几个癌症和化疗引起的慢性疼痛的临床前模型中证明了它们的有效性，所有这些模型都几乎没有中枢神经系统介导的副作用和耐受性发展。在这里，我们提出了一个里程碑驱动的进展计划，即基于sar的支架合成、体外/体内筛选和IND支持研究，以开发用于癌症疼痛治疗的优化PRCB。Specific Aim (SA) 1采用迭代合成方法，结合高通量体外筛选，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性质的新PRCB类似物。SA2采用行业标准的体外检测来评估其溶解度、蛋白质结合、潜在细胞毒性、肝酶诱导和脱靶活性，从而进一步优化PRCB。SA3描述了最有前途的PRCBs的体内口腔癌疼痛抑制、中枢神经系统副作用、药代动力学、药效学靶标参与生物标志物、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SA4阶段推进到由NIH cro进行的全面扩大规模和IND研究，然后进行IND申请和批准。这些研究是开展最佳PRCB治疗口腔癌疼痛的I期单组、双盲、安慰剂对照、剂量递增试验的前提，以确定其安全性、PK、PD和剂量效应，并确认靶标参与。