Development of a MMP Inhibitor for Neuropathic Pain

 描述(申请人提供)：Aquilus制药公司计划通过一种新发现的涉及基质金属蛋白酶-2和9(MMP2，MMP9)的机制，在临床前开发AQU-118，用于治疗口腔面部和一般神经病理性疼痛。AQU-118是一种非异羟肟酸的基质金属蛋白酶抑制剂，对基质金属蛋白酶-2和基质金属蛋白酶-9均有选择性，已被证明可以阻断神经病理性疼痛的脊神经结扎(SNL)和眼眶下神经慢性压迫损伤(CCI-ION)啮齿动物模型中的机械性痛觉异常。第二阶段的目标是扩大AQU-118的合成，测定其在SNL-大鼠模型中的药代动力学和药代动力学(PK/PD)，并在第一年内完成体外安全性研究。第二年将需要对AQU-118的合成放大进行工艺研究和开发(PRD)，最终达到生产GMP的目的，并完成各种Pivotol GLP动物毒性研究。拟议工作的最终目标是迅速开发一种安全有效的药物，用于治疗慢性口面部和一般神经性疼痛，而不会产生上瘾或愉悦的副作用。

 DESCRIPTION (provided by applicant): Aquilus Pharmaceuticals, Inc. proposes to preclinically develop AQU-118 for the treatment of orofacial and general neuropathic pain via a newly discovered mechanism involving matrix metalloproteinases-2 & 9 (MMP-2, MMP-9). AQU-118 is a non-hydroxamic acid containing, MMP inhibitor that is selective for both MMP-2 and MMP-9 and has been shown to block mechanical allodynia in both the spinal nerve ligation (SNL) and the chronic constriction injury of the infraorbital nerve (CCI-IoN) rodent models of neuropathic pain. The goals for Phase II are to scale-up the synthesis of AQU-118, determine its phamacokinetics & phamacodynamics (PK/PD) in the SNL-rat model and complete in-vitro safety studies within the first year. Year two will entail the process research & development (PRD) of the synthetic scale- up of AQU-118 culminating in its GMP manufacture as well completing various pivotol GLP animal toxicity studies. The ultimate goal of the proposed work is to rapidly develop a safe and effective drug for the treatment of chronic orofacial and general neuropathic pain that produces no addictive or euphoric side-effects.