Pre-clinical development of NGP 555 for the prevention of AD

NGP 555预防AD的临床前开发

• 批准号: 8124057
• 负责人: William T Comer
• 金额: $ 28.85万
• 依托单位: NEUROGENETIC PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8124057
• 关键词: Acute; Adverse effects; Affect; Age; Alzheimer disease prevention; Alzheimer' s Disease; American; Amyloid beta-Protein; Behavioral; Binding; Bioavailable; Biological Assay; Biological Markers; Brain; Canis familiaris; Cardiopulmonary; Cells; Chronic; Clinical; Clinical Trials; Confusion; Dementia; Development; Disease; Drug Interactions; Drug or chemical Tissue Distribution; Elderly; Elements; Enzymes; Evaluation; Exhibits; Exposure to; Future; Goals; Goblet Cells; Human; Impaired cognition; In Vitro; Intestines; Investigational Drugs; Investigational New Drug Application; Lead; Memory Loss; Modality; Multienzyme Complexes; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Non-Steroidal Anti-Inflammatory Agents; Oral; Oral Administration; Pathology; Penetration; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma; Preclinical Testing; Prevention; Process; Production; Property; Rattus; Relative (related person); Reporting; Rodent; Safety; Senile Plaques; Senile dementia; Series; Societies; Solid; Solutions; Sulindac Sulfide; Symptoms; System; Testing; Tg2576; Therapeutic; Tissues; Toxic effect; Transgenic Mice; base; cell type; cellular development; cognitive function; cost; drug discovery; drug market; feeding; gamma secretase; genotoxicity; in vivo; inhibitor/antagonist; innovation; neurogenetics; notch protein; novel; pre-clinical; prevent; public health relevance; safety study; small molecule

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common form of senile dementia. An estimated 5.3 million Americans are affected, and this number is increasing yearly. Currently, there is no cure for AD; however, it is widely accepted that inhibiting amyloid plaque formation would be beneficial for the prevention of Alzheimer's disease. Although there are many approaches for the treatment of AD, one novel and innovative approach is to modulate the activity of the key enzyme complex involved in Abeta42 production (a primary component of amyloid plaques), gamma-secretase. Because of the potential for serious side-effects associated with inhibition of gamma-secretase, modulation of its activity was targeted in order to avoid non-specific effects on other gamma-secretase substrates such as the Notch, an essential element for normal cellular development. Our scientific approach utilized a cell-based assay that led to the discovery of a proprietary series of gamma-secretase modulators. Medicinal chemistry followed by in vitro and in vivo optimization efforts led to the identification of the lead compound NGP 328, a small molecule that has been demonstrated to lower Abeta42 both in vitro and in vivo and which promotes the formation of smaller, potentially less toxic Abeta peptides (Abeta37 and Abeta38) without altering the activity of gamma-secretase toward other substrates such as Notch. We propose to do an initial proof of concept study in a non-transgenic rodent in which initial toxicity and safety studies will be conducted. We plan to compare the effects of orally delivered NGP 555 on specific Abeta biomarkers in rat CSF to any Notch-related toxicity to determine a therapeutic window. Additionally, we will identify an appropriate oral or solid delivery system for future toxicity and safety studies. If these studies are successful, we plan to initiate full-fledged pre- clinical development of NGP 555 for the prevention of Alzheimer's disease. In this proposal we plan to identify a therapeutic window for modulating Abeta peptides in rodent CSF to Notch-related histological toxicity (proof of concept study) and to complete pre-clinical development of NGP 555 including the following: 1) Prepare a batch of non-GMP NGP 555 drug substance to support nonclinical studies. 2) Conduct IND-enabling beagle dog cardiopulmonary safety, acute toxicity, and 14-day toxicity studies. 3) Conduct in vivo NGP 555 genotoxicity, drug elimination and tissue distribution studies and conduct drug-drug interaction studies in vitro. These studies are expected to result in filing an Investigational New Drug (IND) application for NGP 555.

描述（由申请人提供）：阿尔茨海默病（AD）是老年痴呆症的最常见形式。估计有530万美国人受到影响，而且这个数字每年都在增加。目前，还没有治愈AD的方法;然而，人们普遍认为抑制淀粉样蛋白斑块的形成将有利于预防阿尔茨海默病。尽管有许多治疗AD的方法，但一种新颖且创新的方法是调节参与A β 42产生（淀粉样斑块的主要组分）的关键酶复合物γ-分泌酶的活性。由于与抑制γ-分泌酶相关的严重副作用的可能性，靶向调节其活性以避免对其他γ-分泌酶底物（如Notch，正常细胞发育的必需元素）的非特异性影响。我们的科学方法利用了一种基于细胞的检测方法，发现了一系列专有的γ-分泌酶调节剂。药物化学以及体外和体内优化工作导致了先导化合物NGP 328的鉴定，NGP 328是一种小分子，已被证明在体外和体内均降低A β 42，并促进形成较小的、潜在毒性较低的A β肽（A β 37和A β 38），而不改变γ-分泌酶对其他底物（如Notch）的活性。我们建议在非转基因啮齿动物中进行初步概念验证研究，其中将进行初步毒性和安全性研究。我们计划将口服递送的NGP 555对大鼠CSF中特定Abeta生物标志物的作用与任何Notch相关毒性进行比较，以确定治疗窗口。此外，我们将确定一个适当的口服或固体输送系统，用于未来的毒性和安全性研究。如果这些研究成功，我们计划启动NGP 555预防阿尔茨海默病的全面临床前开发。在本提案中，我们计划确定调节啮齿动物CSF中Abeta肽至Notch相关组织学毒性的治疗窗口（概念验证研究），并完成NGP 555的临床前开发，包括以下内容：1）制备一批非GMP NGP 555原料药，以支持非临床研究。2)进行IND支持的比格犬心肺安全性、急性毒性和14天毒性研究。3)进行体内NGP 555遗传毒性、药物消除和组织分布研究，并进行体外药物相互作用研究。这些研究预计将导致提交NGP 555的研究性新药（IND）申请。