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

基本信息

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
项目类别：
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

项目摘要

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.

口腔癌疼痛令人衰弱，是临床挑战的重大挑战，部分原因是当前可用疗法中最有效的疗法也受到副作用的限制。虽然化学疗法和放射疗法延长了生存期，但慢性癌症疼痛会导致生活质量差。除了呼吸道，胃肠道和中枢神经系统（CNS）副作用外，由于耐受性，依赖性和阿片类药物诱导的超痛性的发展，护理阿片类镇痛药的长期有效性有限，因此剂量升级通常会导致处方阿片类药物的滥用。因此，对于癌症疼痛的更有效的治疗方法明显未满足，这将具有有利的治疗/副作用比例，尤其是缺乏CNS副作用和当前临床阿片类药物的滥用潜力。我们已经开发了合成的外围限制性大麻素（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CB1受体，它们不会越过血脑屏障，并且我们已经在几种临床前的癌症和化学疗法引起的慢性疼痛的模型中证明了它们的有效性，这几乎缺乏CNS介导的副作用和耐受性的发展。在这里，我们提出了一个基于SAR形式支架的合成，体外/体内筛查的里程碑驱动的进展计划，并为开发优化的PRCB用于癌症疼痛治疗的研究提供了IND促进研究。特定目标（SA）1使用迭代合成方法，以及高通量的体外筛选，评估目标活性，外围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。 SA2利用行业标准的体外测定法来评估溶解度，蛋白质结合，潜在的细胞毒性，肝酶诱导和脱靶活性，以进一步告知PRCB优化。 SA3介绍了体内口腔癌疼痛抑制，CNS副作用，药代动力学，药效目标参与生物标志物，成瘾责任，毒理学和最有前途的PRCB的安全药理学。然后，从这些研究中出现的最佳候选人将在SA4中进步，从NIH CROS进行全面扩展和成分研究，然后进行IND应用和批准。这些研究是第I期，单一组，双盲，安慰剂对照，最佳PRCB剂量升级试验的前提，以确定其安全性，PK，PD和剂量效应，并确认目标参与。