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

 描述(由申请人提供)：这项提议的目标是推进一种口服生物利用的一流的生长抑素受体亚型4选择性候选药物，具有疾病修改属性，用于治疗阿尔茨海默病(AD)。这种“Hit”化合物已被证实可以增强AD和认知衰退小鼠的学习和记忆能力，降低大脑中的β-淀粉样蛋白(A？)寡聚体水平。我们的计划现已推进到Lead优化，这是通过增强Lead系列的“类药物”属性并结合明确的改进标准来实现的，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，可以进行额外的设计调整和测试。目标1：设计和合成。合理的药物设计策略将在计算机模拟、合成和构效关系(SAR)研究中迭代进行，以提高有效性和选择性，降低潜在毒性，并增强口服生物利用度的物理化学性质。合成方法将进一步发展，并在适当的情况下应用于迭代和并行药物化学。目的-2：体外筛选。利用已建立的体外方法，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)将以顺序方式进行评估，以描绘化合物的活性。目的-3：体内/体外评估。符合必要标准的化合物将进入药代动力学评价(静脉注射)。和P.O.)以便进一步描述和识别主要铅。这条线索 将通过慢性假释进行测试。在3xTg小鼠AD模型中，按年龄相关的时间间隔给药，这与神经病理发育和学习/记忆衰退的关键时期相吻合。给药范围将根据药代动力学数据确定。将通过Morris水迷宫、T迷宫和物体识别测试来评估铅化合物对学习和记忆的影响。在最终的行为测试之后，将对皮质和海马区组织进行评估，以描绘与AD病理和拟议的药物机制相关的关键蛋白质/酶的变化。这项研究将使一种一流的AD候选药物进入下一阶段的开发。这项研究的目的是解决国家卫生研究院的优先事项，具体到神经系统疾病的药物发现方面，与候选药物的先导优化有关：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.