Lead optimization of somatostatin-based therapeutic for Alzheimer's Disease

 描述（由申请人提供）：该提案的目标是开发一种口服生物可利用的一流生长激素抑制素受体亚型-4选择性候选药物，具有改善疾病的属性，用于治疗阿尔茨海默病（AD）。这种“命中”化合物已被证实可增强AD和认知能力下降小鼠模型的学习和记忆，并降低大脑中的β-淀粉样蛋白（A β）寡聚体水平。我们的计划现在已经推进到铅优化，这是通过增强铅系列的“药物样”性质与明确定义的进展标准相结合来实现的，分别用于建模、体外筛选和体内/体外验证。这项研究将通过三个具体目标来完成。根据每个目标的结果，可能会进行额外的设计调整和测试。目标1：设计和合成。将采用迭代计算机模拟、合成和构效关系（SAR）研究进行合理的药物设计策略，以增强效价和选择性，降低潜在毒性，并增强口服生物利用度的理化性质。将进一步开发合成方法，并在适当情况下将其应用于迭代和并行药物化学。目的-2：体外筛选。使用已建立的体外方法，将以顺序方式评估关键性质（即溶解性、受体亲和力和选择性、活性、血浆结合、稳定性、渗透性和毒性潜力），以描述化合物的活力。目的-3：体内/离体评估。符合必要标准的化合物将进行药代动力学评价（i. v.和p.o.）用于进一步描绘和识别主要导联。这条线索 将通过慢性p.o.进行检测。在AD的3xTg小鼠模型中，以与神经病理学发展和学习/记忆衰退的关键时期一致的年龄依赖性间隔施用。将根据药代动力学数据确定剂量范围。将通过Morris水迷宫、T迷宫和物体识别测试评估铅化合物对学习和记忆的影响。最终行为测试后，将评价皮质和海马组织，以描述与AD病理学和拟定药物机制相关的关键蛋白质/酶的变化。这项研究将最终推动一流的AD候选药物进入下一个开发阶段。本研究的目的是解决美国国立卫生研究院的优先事项，特别是针对神经系统疾病的药物发现与候选药物先导化合物优化：FOA编号：PAR-13-048。

 DESCRIPTION (provided by applicant): The goal of this proposal is to advance an orally bioavailable first-in-class somatostatin receptor subtype-4 selective drug candidate with disease-modifying attributes for the treatment of Alzheimer's disease (AD). The "hit" compound has been validated to enhance learning and memory in mouse models of AD and cognitive decline, with a reduction of beta-amyloid (Aß) oligomer levels within the brain. Our program has now advanced to lead optimization, which is accomplished through enhancement of "drug-like" properties of the lead series in tandem with well-defined advancement criteria, respective to modeling, in vitro screens and in vivo/ex vivo validation. This study will be accomplished via three specific aims. Based on outcomes within each aim, additional design adjustments and testing may be performed. Aim-1: Design and synthesis. Rational drug design strategies employing iterative in silico modeling, synthesis, and structure-activity relationship (SAR) studies will be conducted to enhance potency and selectivity, reduce potential toxicity, and enhance physiochemical properties for oral bioavailability. Synthetic methods will be further developed and applied to iterative and parallel medicinal chemistry where appropriate. Aim-2: In vitro screens. Using established in vitro methods, critical properties (i.e. solubility, receptor affinity and selectivity, activity, plasma binding, stability, permeability, and toxicity potential will be assessed in a sequential manner to delineate compound viability. Aim-3: In vivo/ex vivo assessments. Compounds meeting necessary criteria will be advanced to pharmacokinetic evaluations (i.v. and p.o.) for further delineation and identification of a primary lead. This lead will be tested via chronic p.o. administration in the 3xTg mouse model of AD at age-dependent intervals that coincide with critical periods of neuropathological development and learning/memory decline. Dosing range will be determined from pharmacokinetic data. Delineation of lead compound impact on learning and memory will be assessed via Morris water-maze, T-maze, and object recognition testing. Following final behavioral testing, cortical and hippocampal tissues will be evaluated to delineate changes in critical proteins/enzymes associated with AD pathology and proposed drug mechanism. This study will culminate in the advancement of a first-in-class AD drug candidate to the next stage of development. The aims of this study address priorities of National Institutes of Health, specific to drug discovery for nervous system disorders respective to drug-candidate lead optimization: FOA number: PAR-13-048.