Development of a MMP Inhibitor for Neuropathic Pain

 描述（由申请人提供）：Aquilus Pharmaceuticals，Inc.提出临床前开发AQU-118，用于通过新发现的涉及基质金属蛋白酶-2&9（MMP-2，MMP-9）的机制治疗口面和全身神经性疼痛。AQU-118是一种不含异羟肟酸的MMP抑制剂，其对MMP-2和MMP-9两者都具有选择性，并且已显示在神经性疼痛的脊神经结扎（SNL）和眶下神经慢性压迫性损伤（CCI-IoN）啮齿动物模型中阻断机械性异常性疼痛。第二阶段的目标是扩大AQU-118的合成，确定其在SNL-大鼠模型中的药效学和药效学（PK/PD），并在第一年内完成体外安全性研究。第二年将进行AQU-118合成规模扩大的工艺研究与开发（PRD），最终实现其GMP生产，并完成各种阿托洛尔GLP动物毒性研究。这项工作的最终目标是快速开发一种安全有效的药物，用于治疗慢性口面和一般神经性疼痛，不会产生成瘾或欣快的副作用。

 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.