Utility of Muscarinic Agonists for Alzheimer's disease

毒蕈碱激动剂治疗阿尔茨海默氏病的用途

• 批准号: 6791804
• 负责人: EDWARD J MCGUIRE
• 金额: $ 33.87万
• 依托单位: COGNITIVE PHARMACEUTICALS, LTD
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-11-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6791804
• 关键词: Alzheimer' s disease; SDS polyacrylamide gel electrophoresis; amyloid proteins; analytical chemistry; anticholinergic agent; brain disorder chemotherapy; calorimetry; cell line; chemical standardization; cholinergic receptors; cytochromes; drug design /synthesis /production; drug interactions; drug metabolism; drug screening /evaluation; enzyme linked immunosorbent assay; high performance liquid chromatography; laboratory rat; liquid chromatography mass spectrometry; muscarine; neuropharmacologic agent; neuropharmacology; pharmacokinetics; pyrimidine analog; receptor binding

DESCRIPTION (provided by applicant): The purpose of this Phase II SBIR proposal is to continue the development of CDD-0102 as a potential treatment for Alzheimer's disease (AD). Accomplishments from the Phase I award included demonstration of the stimulation of alpha-secretase by CDD-0102, identification of the major metabolizing enzymes and the chemical synthesis of one potential metabolite. In AD cholinergic pathways that subserve memory degenerate, and plaques and tangles that are toxic to neurons accumulate in the brain, leading to loss of memory, behavioral disturbances, and eventually death. Existing treatments inhibit the breakdown of the transmitter acetylcholine, improving memory and behavior briefly, but do not attenuate the progression of the disease. CDD-0102 is a selective M1 receptor agonist, meaning that it binds to and activates muscarinic receptors associated with memory pathways, but not other muscarinic receptors, for example, M3 receptors that are responsible for unwanted side effects. CDD-0102 improves memory in an animal model of AD and appears to be safe based on a two-week toxicity study in rats. M1 muscarinic receptors are also linked to pathways that stimulate alpha-secretase activity, thereby preventing the formation of beta-amyloid protein that leads to plaques. The findings indicate that CDD-0102 has the potential to replace acetylcholine at M1 receptors to improve memory and reduce behavioral problems and reduce or prevent the formation of beta-amyloid and thus plaques. The studies proposed in this Phase II SBIR proposal are designed to evaluate further the potential beneficial effects of CDD-0102 and to reach the milestone of filing an Investigational New Drug application with the FDA. CDD-0102 will be synthesized for the studies, incorporating scale-up, process improvements, chemical analysis and analytical standards. Metabolites of CDD-0102 will be identified using frozen human liver cells and microsomes containing individual cytochrome P450 enzymes, as well as rats. Efficacy will be evaluated further, measuring effects on alpha-secretase. Pre-formulation of CDD-0102 will be investigated by selection of the best salt, and measurement of chemical and physical properties of different dosage forms. Additional product testing will be outsourced and performed under Good Laboratory Practice (GLP) standards by reputable firms. The proposed work will allow Cognitive Pharmaceuticals, Ltd. to reach a major milestone in the commercialization of CDD-0102 for the treatment of Alzheimer's disease.

描述（由申请人提供）：该II期SBIR提案的目的是继续开发CDD-0102作为对阿尔茨海默氏病（AD）的潜在治疗方法。第一阶段奖项的成就包括CDD-0102刺激α-分泌酶的刺激，主要代谢酶的鉴定以及一种潜在代谢物的化学合成。在降低记忆退化的AD胆碱能途径中，对神经元有毒的斑块和缠结在大脑中积累，导致记忆力丧失，行为干扰以及最终死亡。现有治疗方法抑制了递质乙酰胆碱的分解，短暂改善记忆力和行为，但不会减弱疾病的进展。 CDD-0102是一种选择性的M1受体激动剂，这意味着它与与记忆途径相关的毒蕈碱受体结合并激活了与记忆途径相关的毒蕈碱受体，而不是其他毒蕈碱受体，例如，导致不必要副作用的M3受体。 CDD-0102改善了AD动物模型中的记忆力，并且根据大鼠的两周毒性研究似乎是安全的。 M1毒蕈碱受体也与刺激α-分泌酶活性的途径有关，从而防止形成β-淀粉样蛋白，从而导致斑块。研究结果表明，CDD-0102有可能替代M1受体处的乙酰胆碱，以改善记忆力并减少行为问题并减少或防止形成β-淀粉样蛋白并因此形成斑块。在此II期SBIR提案中提出的研究旨在进一步评估CDD-0102的潜在有益作用，并达到向FDA提交研究新药应用的里程碑。 CDD-0102将合成用于研究，结合扩大，过程改进，化学分析和分析标准。 CDD-0102的代谢产物将使用含有单个细胞色素P450酶以及大鼠的冷冻人肝细胞和微粒体鉴定。 功效将进一步评估，测量对α-分泌酶的影响。 CDD-0102的预制化将通过选择最佳盐的选择，并测量不同剂型的化学和物理性质。 在良好的实验室实践（GLP）下将外包和执行其他产品测试 信誉良好的公司的标准。拟议的工作将使认知药物有限公司达到 CDD-0102商​​业化治疗阿尔茨海默氏病的主要里程碑。