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

项目总结/摘要 阿尔茨海默病（AD）是一种进行性多因素疾病，影响全球超过5000万人， 是最常见的老年痴呆症迄今为止，没有任何干预措施表明 预防、延迟或治疗AD的治疗功效。近年来，心血管疾病（CVD）和 遗传因素（ApoE 4）已被归因于发展AD的风险增加。这只病态的手臂 肾素血管紧张素系统（RAS）与CVD和AD有关，而保护臂， 包括血管紧张素（1-7）[A（1-7）]、Mas受体和ACE 2已知对这些作用进行反调节。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）， 它还通过上调内源性干细胞群而具有再生作用。临床研究数据 已经表明AD患者中A（1-7）和ACE 2均降低，并且几项体内研究支持 A（1-7）治疗AD的疗效。虽然A（1-7）在AD模型中的作用非常有希望，但其 短半衰期和缺乏口服生物利用度使其开发为治疗方式具有挑战性。为了 为了克服这一缺点，本实验室开发了A（1-7）的等效小分子类似物， RASRx 1902和RASRx 1911。RASRx 1902和RASRx 1911已被证明可以减少炎症和OS 在靶器官中以及对受损组织具有再生作用。我们实验室最近的一项研究表明 RASRx 1902和RASRx 1911能够改善认知功能，并降低大脑中的OS。 高血压诱导的认知功能障碍（横向主动脉缩窄[TAC]）的小鼠模型。自从马斯 已知激动作用在AD中具有有益作用，我们假设这些分子可以被开发为 一种治疗AD和相关痴呆的潜在新疗法。本提案的主要目的是 将推进一种小分子Mas激动剂的开发，以提交研究新药 应用（IND）通过以下方式治疗AD和相关痴呆：1.口服药物的疗效评价 TAC和AD小鼠模型中的RASRxl 902和RASRxl 911（5xFAD和ApoE 4）; 2.疗效评估 RASRx 1902在TAC-ApoE 4小鼠中的表达，3.根据药品生产质量管理规范生产的一种Mas激动剂的规模放大 规范（GMP）;开发一种Mas激动剂的制剂用于I期临床试验; 5.完成 ADME、（PK）和IND启用毒理学研究; 6. IND前准备和IND文件; 7.进行 一个前IND会议;和8.提交IND。本文提出的研究响应PAS 18-820，以开发 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”.