Development of KLS-13019 for Neuropathic Pain

开发用于治疗神经性疼痛的 KLS-13019

• 批准号: 10704175
• 负责人: Douglas Eric Brenneman
• 金额: $ 100.18万
• 依托单位: KANNALIFE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10704175
• 关键词: Acute; Affect; Afferent Neurons; Anti-Inflammatory Agents; Antiinflammatory Effect; Attenuated; Biological Assay; Biological Availability; Biological Markers; Calcium; Canis familiaris; Cannabidiol; Cannabis sativa plant; Cardiac; Chemicals; Chemotherapy-induced peripheral neuropathy; Chronic; Clinical Trials; Collaborations; Data; Dependence; Development; Dose; Drug Kinetics; Etiology; Evaluation; Exposure to; Formulation; GPR55 receptor; Grant; High Pressure Liquid Chromatography; Histopathology; Homeostasis; Human; Impairment; In Vitro; Inflammation; Inflammatory; Laboratories; Legal patent; Mechanics; Mediating; Medical; Methods; Mitochondria; Modality; Modeling; Morphine; Nociception; Opiate Addiction; Opioid; Oral; Oral Administration; Oxidative Stress; Oxidative Stress Induction; Paclitaxel; Pain; Pain management; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Preparation; Prevention; Process; Production; Property; Quality of life; Rattus; Reference Standards; Regulation; Reporting; Residual state; Risk; Role; Safety; Self Administration; Series; Small Business Technology Transfer Research; Solvents; Spinal Ganglia; Tactile; Toxic effect; Toxicokinetics; Toxicology; Validation; Vendor; Work; abuse liability; analog; analytical method; antagonist; beta-arrestin; cancer therapy; cannabinoid receptor; chronic pain management; cytokine; effective therapy; genotoxicity; improved; in vivo; in vivo evaluation; inflammatory marker; mitochondrial dysfunction; mouse model; nervous system disorder; neural; neuroinflammation; neuroprotection; neurotoxicity; pain sensitivity; painful neuropathy; pharmacologic; pre-Investigational New Drug meeting; prescription opioid; preservation; prevent; process optimization; respiratory; success

Neuropathic pain remains a challenging neurologic disorder that adversely affects quality of life and presents a large unmet medical need. Chemotherapy-induced peripheral neuropathy (CIPN) is a chronic, severely debilitating consequence of cancer therapy for which there are no effective management strategies. Upwards of 80-97% of CIPN patients reported using prescription opioids for this pain management. Mitochondrial dysfunction, oxidative stress, and inflammation have all been implicated in CIPN etiology. In a mouse model of paclitaxel-induced pain sensitivity, we have previously reported that cannabidiol (CBD) is effective in preventing the onset of this treatment consequence. Now a new CBD analogue (KLS-13019) has been discovered in our laboratory that has improved drug-like properties in comparison to CBD, while retaining neuroprotective properties. In our Phase 1 STTR, the previous neuroprotective effects of CBD to prevent the development of mechanical sensitivity in the presence of paclitaxel were confirmed and extended to the structural analogue KLS- 13019. Both compounds were equi-effective and equi-potent following oral administration. In the reversal studies, CBD did not attenuate mechanical sensitivity when administered after CIPN was induced by paclitaxel treatment. However, KLS-13019 significantly and dose-dependently attenuated tactile sensitivity in the reversal paradigm and was more potent and effective than treatment with morphine. Importantly, KLS-13019 also attenuated the reinforcing properties of morphine in a mouse model of morphine self-administration. In vitro, we have shown that KLS-13019 and CBD protect against paclitaxel-induced oxidative stress in dorsal root ganglia cultures, and that a mechanism underlying this neuroprotection is regulation of intracellular calcium via the mitochondrial Na+/Ca++ exchanger-1 (mNCX-1). Our central hypothesis is that administration of CBD or KLS-13019 preserves Ca2+ homeostasis by promoting activity of the mNCX-1. Furthermore, our new data demonstrates that the putative cannabinoid receptor GPR55 is induced following paclitaxel treatment and contributes to sensory neuron toxicity and inflammation that can be reversed by KLS-13019, but not CBD. These studies support a pro- nociceptive, pro-inflammatory role for GPR55 that mediates pain associated with CIPN. We predict bi-modal pharmacological effects of KLS-13019 that can both increase viability of sensory neurons exposed to paclitaxel acutely and decrease inducible GPR55 that contributes to long-term neuroinflammation. Evidence has been obtained that KLS-13019 is an antagonist to GPR55 as shown in a β-arrestin assay. In Phase 2, we will optimize the process to prepare KLS-13019, develop analytical methods, optimize formulation, and evaluate in pharmacokinetic studies. A fully battery of genotoxicity, safety pharmacology, toxicokinetic, and toxicology reports will be completed. KLS-13019 will be evaluated in a rat models of CIPN, tolerance, impairment, and abuse liability. At the conclusion of this grant, the data will be submitted to the FDA and a pre-IND meeting will be completed.

神经性疼痛仍然是一种具有挑战性的神经系统疾病，对生活质量产生不利影响

项目成果

Efficient Syntheses of KLS-13019 Using Palladium Mediated Cross Couplings.

使用钯介导的交叉偶联有效合成 KLS-13019。

• DOI: 10.1016/j.tetlet.2023.154369
• 发表时间: 2023
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Kinney,WilliamA;McDonnell,MarkE;Freeman,Stanley;Simons,Nick;Han,Chao;Yang,Lanyi
• 通讯作者: Yang,Lanyi