CRF RECEPTOR ANTAGONISTS IN NEUROPROTECTION

CRF 受体拮抗剂在神经保护中的作用

• 批准号: 6142106
• 负责人: ALAN C FOSTER
• 金额: $ 63.56万
• 依托单位: NEUROCRINE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6142106
• 关键词: anorexia; cerebral ischemia /hypoxia; combinatorial chemistry; corticotropin releasing factor; drug design /synthesis /production; hormone receptor; inhibitor /antagonist; method development; migraine; molecular cloning; neuropharmacology; neuroprotectants; oral administration

Corticotropin releasing factor (CRF) is a primary co-ordinator of the body's response to stress through its endocrine and neurotransmitter actions. The effects of CRF are mediated by two receptor sub-types, CRF1 and CRF2. CRF antagonists may protect the brain during stroke since mixed CRF1/CRF2 peptide antagonists reduce ischemia-induced neuronal degeneration in animal models. In Phase studies we demonstrated that mRNA and peptide for CRF are elevated in the rodent brain following cerebral ischemia, and that CRF1 receptor antagonists are neuroprotective in animal stroke models. However, CRF may have protective effects through CRF2 receptors on cerebral blood vessels. Consequently, for neuroprotection, a CRF1 antagonist is the optimal approach. Neurocrine has identified novel small molecule, CRF1 receptor-selective antagonists which cross the blood-brain barrier after intravenous administration. A major goal of the Phase Il studies is to optimize a CRF1 receptor antagonist for advancement to clinical trials in stroke. Furthermore, a CRF1 receptor antagonist will be characterized in various animal models of stroke, to provide information which will guide the clinical studies. In addition, studies will be undertaken which are designed to elucidate the precise cellular mechanisms which give rise to CRF-induced neuronal degeneration and protection by CRF1 receptor antagonists. PROPOSED COMMERCIAL APPLICATION: According to the American Heart Association, stroke is the third leading cause of death in the U.S.A. with approximately 500,000 new cases each year and a total of 4 million affected individuals. It is the leading cause of serious long-term disability amongst Americans. The only currently approved therapy in the U.S.A. is the thrombolytic agent, tPA. Consequently, there is a large unmet medical need for effective drugs to reduced the devastating consequences of stroke on brain function. Neurocrine has exclusive rights from the Salk Institute to one issued patent to the cloned CRF1 receptor and its homologs, and Neurocrine owns an issued patent on the CRF2 receptor and its homologs. Neurocrine also has several patent applications in place for composition of matter protection on their small molecule CRF receptor antagonists. The proposed Phase II studies will identify a small molecule CRF1 selective antagonist suitable for acute intervention in stroke and provide a detailed characterization of its neuroprotective properties in animal models and its mechanism of action. This information will guide clinical studies designed to evaluate the safety and efficacy of such a compound in human stroke, and ultimately define the commercial application.

皮质激素释放因子（CRF）是人体通过其内分泌和神经递质作用对压力反应的主要协调因子。 CRF的作用是由两个受体亚型CRF1和CRF2介导的。 CRF拮抗剂可以在中风过程中保护大脑，因为混合的CRF1/CRF2肽拮抗剂可减少动物模型中缺血诱导的神经元变性。在阶段研究中，我们表明，脑缺血后，啮齿动物脑中的mRNA和肽在啮齿动物大脑中升高，并且CRF1受体拮抗剂在动物卒中模型中具有神经保护作用。但是，CRF可能通过CRF2受体对脑血管具有保护作用。因此，对于神经保护作用，CRF1拮抗剂是最佳方法。 Neurocrine确定了新型的小分子CRF1受体选择性拮抗剂，这些拮抗剂在静脉内给药后穿过血脑屏障。 IL研究期的主要目标是优化CRF1受体拮抗剂，以促进中风临床试验。此外，将在各种动物中风模型中表征CRF1受体拮抗剂，以提供指导临床研究的信息。此外，还将进行研究，旨在阐明CRF1受体拮抗剂引起CRF诱导的神经元变性和保护的精确细胞机制。拟议的商业应用程序：根据美国心脏协会的说法，中风是美国第三大死亡原因。每年约有500,000例新病例，共有400万受影响的人。这是美国人严重长期残疾的主要原因。目前在美国唯一批准的治疗是溶栓剂TPA。因此，对有效药物的医疗需求很大，可以减少中风对脑功能的破坏性后果。 Neurocrine拥有Salk Institute的专有权，并获得了克隆的CRF1受体及其同源物的专利，并且Neurocrine拥有对CRF2受体及其同源物的专利。 Neurocrine在其小分子CRF受体拮抗剂上还采用了几项专利申请，以组成物质保护。拟议的II期研究将确定一个小分子CRF1选择性拮抗剂，适合于中风急性干预，并详细描述了其在动物模型中的神经保护特性及其作用机理。该信息将指导旨在评估这种化合物在人类中风中的安全性和功效的临床研究，并最终定义商业应用。