Refinement of lead compounds to modulate water permeability through AQP4

描述（由申请人提供）：脑水肿（及其在脊髓中的对应物）是中风、创伤性脑损伤、创伤性脊髓损伤和细菌性脑膜炎引起的损伤的主要原因。中风是美国第三大死亡原因，也是导致残疾的主要原因。不幸的是，很少有治疗脑和脊髓水肿的方法，而且这些方法的疗效有限。脑和脊髓水肿发生的核心是位于星形细胞端足的水通道水通道蛋白-4 (AQP4)，该通道在血脑屏障（BBB）处包裹中枢神经系统血管。AQP4在缺血、创伤性脑损伤和其他多种与炎症相关的中枢神经系统病理中上调。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优于野生型小鼠，这使得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，不仅可以渗透水，还可以溶解气体（CO2, O2， NO）。事实上，上述病理中AQP4的上调可能对血脑屏障O2通透性最大化有有益作用，但其副作用是渗透性水通透性增加，易导致脑水肿。Aeromics的长期目标是开发一种药物，通过阻断AQP4的水渗透性来治疗脑水肿，使气体渗透性保持不变。在第一阶段的SBIR中，Aeromics已经完成了其主要目标：(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)从四个不同的结构类别中识别6个命中。这项II期SBIR申请的目标是：(1)优化发现阶段的安全性和有效性筛选，(2)使用可用的化合物和一些药物化学合成来提炼引线，生成适合体内测试的几种化合物，(3)进行体内药理学原理证明，(4)确定作用机制。拟议的工作将为Aeromics的II期续期做准备，其中包括额外的药物化学，以及提交IND申请治疗中风性脑水肿所需的临床前工作。

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.