Mitigating Taxol-Induced Neuropathy through Modulation of the NMDA Receptor

 描述（由申请人提供）：紫杉醇（紫杉醇）是最广泛使用的化疗药物之一，是卵巢癌、乳腺癌、肺癌和结肠癌的一线治疗药物。尽管紫杉醇具有良好的抗癌特性，但已知紫杉醇会引起化疗诱导的周围神经病变（CIPN）。CIPN影响大约30% - 50%的所有化疗患者，并且神经性疼痛可能如此严重，以至于在某些情况下，必须停止化疗治疗。CIPN患者的治疗选择目前非常有限，因此减轻CIPN影响的新方法可能具有显著的临床影响。 Naurex正在研究解决CIPN的新方法。该公司已经开发出一类新型的无毒，口服生物可利用的化合物，调节N-甲基D-天冬氨酸受体（NMDAR）内的谷氨酸能系统。NMDAR参与突触可塑性的调节，并且已知神经性疼痛导致突触可塑性的失调。我们的初步数据显示，Naurex的NMDAR部分激动剂在CIPN的大鼠紫杉醇模型中显示出剂量依赖性镇痛作用。从这些初步研究中鉴定出一种先导化合物NRX-2922，其除了在大鼠紫杉醇模型中具有优异的活性外，还显示出理想的药物特性。该I期SBIR项目的范围是进行临床前研究，以进一步评估NRX-2922缓解CIPC的治疗潜力。为此，我们的具体目标是：目标1建立NRX-2922的剂量反应。目的#2评价NRX-2922预防和治疗CIPN的治疗潜力。目的#3评价NRX-2922与紫杉醇联合给药的药代动力学和毒性。该I期项目的成功完成将建立NRX-2922的有效给药方案，为后续IND使能研究以及临床试验方案提供信息。鉴于紫杉醇的广泛使用及其作为化疗剂的有效性，减少与其使用相关的主要副作用的潜力在肿瘤学领域将是非常重要的。

 DESCRIPTION (provided by applicant): Taxol (paclitaxel) is the one of the most widely used chemotherapy agents, and is a first-line treatment for ovarian, breast, lung, and colon cancer. Despite its well-documented anti-cancer properties, taxol is known to cause chemotherapy-induced peripheral neuropathy (CIPN). CIPN affects approximately 30% - 50% of all chemotherapy patients, and the neuropathic pain can be so severe that in some cases, chemotherapy treatments must be discontinued. Therapeutic options for patients with CIPN are currently very limited, and so a new approach for mitigating the effects of CIPN could have a significant clinical impact. Naurex is investigating a new approach to addressing CIPN. The company has developed a novel class of non-toxic, orally bioavailable compounds that modulate the N-methyl D-aspartate receptor (NMDAR) within the glutamatergic system. The NMDAR is involved in regulation of synaptic plasticity, and it is known that neuropathic pain results in the dysregulation of synaptic plasticity. Our preliminary data shows that Naurex's NMDAR partial agonists display a dose-dependent analgesic effect in a rat Taxol model of CIPN. A lead compound, NRX-2922, was identified from these initial studies that displays desirable pharmaceutical properties in addition to excellent activity in the rat Taxol model. The scope of this Phase I SBIR project is to conduct pre-clinical studies to further evaluate the therapeutic potential of NRX-2922 for mitigating CIPN. To this end, our Specific Aims are: Aim #1 Establish dose response of NRX-2922. Aim #2 Evaluate NRX-2922's therapeutic potential for prevention and treatment of CIPN. Aim #3 Evaluate pharmacokinetics and toxicity of NRX-2922 in combination with Taxol. Successful completion of this Phase I project will establish effective dosing regimens of NRX-2922 that will inform follow-on IND enabling studies as well as clinical trial protocols. Given the widespread use of taxol, and its proven effectiveness as a chemotherapeutic agent, the potential to reduce the main side-effect associated with its usage would be highly significant in the field of oncology.