Refinement of lead compounds to modulate water permeability through AQP4

描述(申请人提供)：脑水肿(和脊髓中的相应部分)是中风、创伤性脑损伤、创伤性脊髓损伤和细菌性脑膜炎造成损害的主要原因。在美国，仅中风一项就是第三大致死原因和第一大致残原因。不幸的是，很少有治疗脑和脊髓浮肿的方法可供选择，而且疗效有限。脑和脊髓水肿的中心是星形细胞末端足部的H2O通道水通道蛋白-4(AQP4)，它包裹着血脑屏障(BBB)处的CNS血管。AQP4在缺血、创伤性脑损伤和其他一系列与炎症相关的中枢神经系统病理中表达上调。但是，矛盾的是，在缺血性中风、视网膜缺血和细菌性脑膜炎的实验模型中，AQP4缺失小鼠的表现明显好于它们的野生型小鼠，这使AQP4成为一个有吸引力的药物靶点。本提案的一个独特方面是认识到AQP是双功能蛋白质，不仅可以渗透到水中，而且还可以溶解气体(二氧化碳、O2、NO)。事实上，在上述病理中，AQP4的上调可能具有使血脑屏障最大限度地提高O2通透性的有益效果，同时也有增加渗透水通透性和易于发生脑水肿的副作用。Aerology的长期目标是开发一种药物，通过阻断AQP4的透水性，保持气体透过性不变，治疗脑水肿。在其第一阶段SBIR中，Aerology已经实现了其主要目标：(A)开发非常成功的高通量筛选(HTS)，(B)开发适当的反筛选，以及(C)识别来自四个不同结构类别的6个命中。这一第二阶段SBIR应用的目标是：(1)优化发现阶段的安全性和有效性筛选，(2)使用可用化合物和一些药物化学合成来提炼引线，产生几种适合体内试验的化合物，(3)进行体内药理学原理验证，以及(4)确定作用机制。拟议的工作将为第二阶段的更新做好准备，其中将包括额外的药物化学，以及提交IND申请治疗中风引起的脑水肿所需的临床前工作。 公共卫生相关性： 脑(脑水肿)和脊髓肿胀是中风、创伤性脑/脊髓损伤和细菌性脑膜炎造成损害的主要原因。不幸的是，只有少数几种治疗方案可用于治疗这种浮肿，而且疗效有限。在其第一阶段的SBIR中，Aerology开发了一项技术，以确定在保持向大脑的氧气输送的同时治疗脑水肿的新药，实际上在4个药物家族中发现了6种新药。在这一第二阶段的SBIR中，Aerology计划利用这些信息来创造新药，并在脑水肿和中风的动物模型上进行测试。下一步将是进一步提炼药物，并准备进行人体试验。

DESCRIPTION (provided by applicant): Cerebral edema (and its counterpart in the spinal cord) is a major contributor to the damage caused by stroke, traumatic brain injury, traumatic spinal-cord injury, and bacterial meningitis. Stroke alone is the third leading cause of death in the USA and the leading cause of disability. Unfortunately, few treatment options are available for cerebral and spinal-cord edema, and these are of limited efficacy. Central in the development of cerebral and spinal-cord edema is the H2O channel aquaporin-4 (AQP4) in the astrocytic end feet that envelope CNS blood vessel at the blood-brain barrier (BBB). AQP4 is upregulated by ischemia, traumatic brain injury, and a diverse array of other CNS pathologies associated with inflammation. But, paradoxically, AQP4- null mice do substantially better than their wild-type counterparts in experimental models of ischemic stroke, retinal ischemia, and bacterial meningitis, making AQP4 an attractive drug target. A unique aspect of the present proposal is the recognition that the AQPs are bifunctional proteins that are permeable not only to water, but also to dissolve gases (CO2, O2, NO). Indeed, the upregulation of AQP4 in the aforementioned pathologies may have the beneficial effect of maximizing O2 permeability across the BBB, with the side effect of increasing osmotic water permeability and predisposing to cerebral edema. The long-term goal of Aeromics is to develop a drug that treats cerebral edema by blocking the water permeability of AQP4, leaving gas permeability intact. In its Phase I SBIR, Aeromics already accomplished its major goals of (a) developing a very successful high-throughput screen (HTS), (b) developing appropriate counterscreens, and (c) identifying 6 hits from four different structural classes. The goals of this Phase II SBIR application are to: (1) optimize discovery-stage safety and efficacy screens, (2) use available compounds and some synthesis for medicinal chemistry to refine leads, generating several compounds appropriate for in-vivo testing, (3) perform in-vivo pharmacologic proof of principle, and (4) determine mechanism of action. The proposed work will prepare Aeromics for a Phase II renewal that will include additional medicinal chemistry, as well as the preclinical work necessary for filing an IND application for treating stroke-induced cerebral edema. PUBLIC HEALTH RELEVANCE: Swelling of the brain (cerebral edema) and spinal cord is a major contributor to the damage caused by stroke, traumatic brain/spinal-cord injury, and bacterial meningitis. Unfortunately, only a few treatment options are available for such edema, and these are of limited efficacy. In its Phase I SBIR, Aeromics developed technology to identify new drugs for treating cerebral edema while maintaining the oxygen delivery to the brain, and in fact discovered 6 new drugs in 4 drug families. In this Phase II SBIR, Aeromics plans to use this information to create new drugs that it will test in animal models of cerebral edema and stroke. The next step will be to refine the drugs further and prepare them for human testing.