Refinement of lead compounds to modulate water permeability through AQP4

精制先导化合物以通过 AQP4 调节水渗透性

• 批准号: 8249441
• 负责人: Marc F Pelletier
• 金额: $ 74.51万
• 依托单位: AEROMICS, INC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249441
• 关键词: Acute; Adverse effects; Altitude Sickness; American; Animal Model; Astrocytes; Bacterial Meningitis; Binding Sites; Biological Assay; Blood - brain barrier anatomy; Blood Vessels; Boron; Brain; Brain Edema; Budgets; Carbon Dioxide; Cause of Death; Cerebral Edema; Cerebrum; Cessation of life; Chemicals; Clinical; Computer Simulation; Data; Development; Drug Delivery Systems; Drug Design; Edema; Experimental Models; Family; Figs - dietary; Funding; Future; Gases; Goals; Human; In Vitro; Inflammation; Intracerebral Pressures; Ischemia; Ischemic Stroke; Kinetics; Knock-out; Knockout Mice; Laboratories; Laboratory Finding; Lead; Left; Legal patent; Location; Mammalian Cell; Mediating; Medical; Meningitis; Microfluidic Microchips; Modeling; Movement; National Institute of Neurological Disorders and Stroke; Neurologist; Outcome; Oxygen; Pathology; Pathway interactions; Patients; Perfusion; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phenotype; Positioning Attribute; Proteins; R43 grant; Recurrence; Route; Safety; Series; Site-Directed Mutagenesis; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Spinal Cord; Spinal cord injury; Staging; Stroke; Structure; Structure-Activity Relationship; Techniques; Technology; Testing; Tissues; Traumatic Brain Injury; Up-Regulation; Validation; Water; Work; aquaporin 4; base; combinatorial chemistry; commercialization; cost; counterscreen; disability; foot; high throughput screening; improved; in vivo; inhibitor/antagonist; injured; molecular dynamics; monomer; novel; pre-clinical; programs; public health relevance; retinal ischemia; spinal cord and brain injury; tumor; water channel

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.

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，脑水肿和脊髓水肿的治疗选择很少，而且疗效有限。脑和脊髓水肿发展的中心是在血脑屏障（BBB）处包裹CNS血管的星形胶质细胞末端足中的H2O通道水通道蛋白-4（AQP 4）。AQP 4被局部缺血、创伤性脑损伤和多种与炎症相关的其他CNS病理上调。但是，矛盾的是，AQP 4- null小鼠在缺血性中风，视网膜缺血和细菌性脑膜炎的实验模型中比野生型小鼠表现得更好，使AQP 4成为一个有吸引力的药物靶点。本发明的一个独特方面是认识到AQP是双功能蛋白质，其不仅对水是可渗透的，而且对溶解气体（CO2、O2、NO）也是可渗透的。事实上，在上述病理中AQP 4的上调可能具有使O2穿过BBB的渗透性最大化的有益效果，具有增加渗透水渗透性和诱发脑水肿的副作用。Aeromics的长期目标是开发一种药物，通过阻断AQP 4的水渗透性来治疗脑水肿，使气体渗透性保持完整。在其第一阶段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）从四种不同的结构类别中鉴定出6种命中物。该II期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）使用可用化合物和药物化学的一些合成来完善先导化合物，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，以及（4）确定作用机制。拟议的工作将为Aeromics的第二阶段更新做准备，其中将包括额外的药物化学，以及提交治疗中风引起的脑水肿的IND申请所需的临床前工作。 公共卫生相关性： 脑肿胀（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引起的损伤的主要原因。不幸的是，只有少数治疗选择可用于这种水肿，这些都是有限的疗效。在其第一阶段SBIR中，Aeromics开发了一种技术，用于识别治疗脑水肿的新药，同时维持向大脑的氧气输送，实际上发现了4个药物家族中的6种新药。在第二阶段SBIR中，Aeromics计划利用这些信息来开发新药，并在脑水肿和中风的动物模型中进行测试。下一步将是进一步完善药物，并准备进行人体试验。