IND Enabling Studies for RASRx 1902, a novel Mas receptor agonist, for treatment of cognitive impairment in patients at risk for Alzheimer's disease.

项目摘要/摘要 阿尔茨海默病(AD)是一种进行性多因素疾病，影响全球5000多万人， 是晚年最常见的痴呆症。到目前为止，没有任何干预措施证明是实质性的。 预防、延迟或治疗阿尔茨海默病的疗效。近年来，无论是心血管疾病(CVD)还是 遗传因素(ApoE4)被认为是AD发病风险增加的原因。人的病态手臂 肾素血管紧张素系统(RAS)与心血管疾病和阿尔茨海默病都有关系，而保护性臂， 已知包括血管紧张素(1-7)[A(1-7)]、Mas受体和ACE2在内的血管紧张素转换酶可反向调节这些效应。A(1- 7)，通过Mas受体，已知在几种疾病状态下减少炎症和氧化(OS)，并 它还通过上调内源性干细胞群起到再生作用。来自临床研究的数据 已表明AD患者的A(1-7)和ACE2均减少，几项体内研究支持 A(1-7)治疗AD的疗效观察虽然A(1-7)在AD模型中的作用非常有希望，但其 较短的半衰期和缺乏口服生物利用度使其发展成为一种治疗方式具有挑战性。为了 克服这一缺点，我们实验室开发出了一种等价的A(1-7)小分子类似物， RASRx1902和RASRx1911。RASRx1902和RASRx1911已被证明可以减少炎症和OS 对靶器官也有影响，对受损组织有再生作用。我们实验室最近的一项研究表明 RASRx1902和RASRx1911能够改善认知功能并减少大脑中的OS 高血压引起的认知功能障碍的小鼠模型(横动脉收缩[TAC])。自马斯以来 激动剂已知对AD有有益的影响，我们假设这些分子可以发展为 一种潜在的治疗AD和相关痴呆的新疗法。这项提案的主要目标是 正在推进一种小分子MAS激动剂的开发，以提交研究新药 应用(IND)治疗阿尔茨海默病及相关痴呆通过：1.评价口服药的疗效 RASRx1902和RASRx1911在TAC和AD小鼠模型(5xFAD和ApoE4)中的作用；2.疗效评价 RASRx1902在TAC-ApoE4小鼠体内的应用，3.一种MAS激动剂的放大生产 实践(GMP)；4.为I期临床试验开发一种MAS激动剂配方；5.完成 ADME，(PK)和支持IND的毒理学研究；6.准备IND前和IND文件；7.进行 IND前会议；以及8.IND的备案。本文提出的研究是响应PAS 18-820而开发的 并评估预防阿尔茨海默病(AD)、减缓其进展或治疗其认知和 行为症状“。

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a progressive multifactorial disease affecting more than 50 million people worldwide, and is the most common dementia of late-life. To date, no interventions have demonstrated substantial therapeutic efficacy to prevent, delay or treat AD. In recent years, both cardiovascular disorders (CVD) and genetic factors (ApoE4) have been attributed to an increased risk of developing AD. The pathological arm of the Renin Angiotensin System (RAS) has been implicated in both CVD and AD, whereas the protective arm, including Angiotensin (1-7)[A(1-7)], Mas receptor and ACE2 are known to counter-regulate these effects. A(1- 7), through the Mas receptor, is known to reduce inflammation and oxidative (OS) in several disease states and it also has regenerative effects by upregulating endogenous stem cell populations. Data from clinical studies have shown that both A(1-7) and ACE2 are reduced in AD patients and several in-vivo studies support the efficacy of A(1-7) in treating AD. While the effects of A(1-7) in AD models have been extremely promising, its short half-life and lack of oral bioavailability make it challenging to develop as a therapeutic modality. In order to overcome this shortcoming, our lab has developed an equipotent small molecule analogues of A(1-7), RASRx1902 and RASRx1911. RASRx1902 and RASRx1911 have been shown to reduce inflammation and OS in target organs as well as having a regenerative effect on damaged tissues. A recent study from our lab showed that RASRx1902 and RASRx1911 were able to improve cognitive function as well as reduce OS in the brain in a mouse model of hypertension induced cognitive dysfunction (transverse aortic constriction [TAC]). Since Mas agonism is known to have a beneficial effect in AD, we hypothesize that these molecules can be developed as a potential new therapeutic for the treatment of AD and related dementias. The primary objective of this proposal are to advance development of one small molecule Mas agonist to submission of an Investigation New Drug Application (IND) for the treatment of AD and related dementias through: 1. Evaluation of the oral efficacy of RASRx1902 and RASRx1911 in TAC and AD mouse models (5xFAD & ApoE4); 2. Assessment of the efficacy of RASRx1902 in TAC-ApoE4 mice, 3. Scale up of one Mas agonist manufactured under Good Manufacturing Practices (GMP); 4. Development of a formulation of one Mas agonist for Phase I clinical trial; 5. Completion of ADME, (PK) and IND-enabling Toxicology studies; 6. Preparation Pre IND and IND Documentation; 7. Conduct of a Pre IND meeting; and 8. Filing of an IND. Research proposed herein is responsive to PAS 18-820 to develop and evaluate therapies “that prevent Alzheimer's disease (AD), slow its progression or treat its cognitive and behavioral symptoms”.