Development of KLS-13019 for Neuropathic Pain

神经病理性疼痛仍然是一种具有挑战性的神经系统疾病，其对生活质量产生不利影响， 未满足的医疗需求。化疗引起的周围神经病变（CIPN）是一种慢性、严重的 癌症治疗的衰弱后果，没有有效的管理策略。超过 80-97%的CIPN患者报告使用处方阿片类药物进行疼痛管理。线粒体 功能障碍、氧化应激和炎症都与CIPN病因有关。的小鼠模型中 紫杉醇诱导的疼痛敏感性，我们以前曾报道大麻二酚（CBD）是有效的预防 这种治疗后果的开始。现在，在我们的研究中发现了一种新的CBD类似物（KLS-13019）。 与CBD相比，实验室改善了药物样特性，同时保留了神经保护作用。 特性.在我们的1期STTR中，CBD以前的神经保护作用，以防止发展， 在紫杉醇存在下的机械敏感性得到证实，并扩展到结构类似物KLS- 13019.两种化合物在口服给药后具有等效性和等效性。在逆转研究中， CBD并没有减弱机械敏感性时，CIPN诱导紫杉醇治疗后给药。 然而，KLS-13019在逆转范例中显著且剂量依赖性地减弱触觉敏感性 并且比用吗啡治疗更有效。重要的是，KLS-13019还减弱了 在吗啡自我给药的小鼠模型中加强吗啡的性质。在体外，我们已经证明 KLS-13019和CBD可以保护背根神经节培养物免受紫杉醇诱导的氧化应激，并且 这种神经保护的机制是通过线粒体调节细胞内钙离子， Na+/Ca++交换体-1（mNCX-1）。我们的中心假设是CBD或KLS-13019的施用保留了 通过促进mNCX-1的活性实现Ca 2+稳态。此外，我们的新数据表明， 紫杉醇治疗后，推定的大麻素受体GPR 55被诱导，并有助于感觉神经元 KLS-13019可以逆转毒性和炎症，但CBD不能。这些研究支持一个亲- 介导与CIPN相关的疼痛的GPR 55的伤害感受性促炎作用。我们预测双峰 KLS-13019的药理学作用既可以增加暴露于紫杉醇的感觉神经元的活力， 急性和减少诱导型GPR 55，有助于长期神经炎症。证据 如β-抑制蛋白测定所示，KLS-13019是GPR 55的拮抗剂。在第二阶段，我们将优化 介绍了制备KLS-13019、开发分析方法、优化处方和评价 药代动力学研究。一整套遗传毒性、安全药理学、毒代动力学和毒理学 报告将完成。KLS-13019将在CIPN、耐受性、损伤和耐受性的大鼠模型中进行评价。 滥用责任在该授权结束时，数据将提交给FDA，IND前会议将 完成。

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.