Development of First-in-Class PDE5/HAT Directed LigandsModulating Molecular Pathways involved in Synaptic Plasticity

阿尔茨海默病(AD)是一种复杂的、多因素的疾病，具有重大的健康和经济社会影响 影响，因为目前还没有有效对抗这种疾病的药物。AD的特点是突触受损 可塑性导致海马区依赖记忆缺陷，人们发现这种记忆出现在 淀粉样斑块的堆积和神经细胞的死亡。这一观察表明，干预措施针对 调节突触可塑性的生物途径可能提供一种减缓、阻止和/或防止 神经退行性变过程的进展。这项建议的目标是确定一流的小型 具有增强突触可塑性的双靶点活性的分子。在初步研究中，我们发现 两个不同的分子靶点，磷酸二酯酶5(PDE5)和组蛋白乙酰转移酶(HAT)在 突触可塑性。我们开发了小分子PDE5抑制剂和HAT激活剂，它们能够拯救 小鼠海马片突触可塑性受损。在一项概念验证研究中，我们证明了 PDE5抑制剂和HAT激活剂联合治疗可使突触获救率提高6倍 与单独使用这两种化合物处理相比，可塑性更好。这些发现表明，调节这些 参与AD的两个靶点提供了比单一靶点治疗更有效的治疗方法。在这项提案中，我们 计划测试通过新合成的单个分子调节PDE5和HAT活性的假设 导致了一种新的AD治疗方法。将使用多目标定向配基的方法来获得PDE5 抑制剂/HAT激活剂药物分子。这种方法已经成为一种有益的治疗方法。 复杂的疾病，并在综合治疗方面显示出若干优势，包括增加 治疗效果，减少药物与药物的相互作用，简化用药方案。具体来说，我们将测试我们的 假设通过以下具体目标：1)设计和合成一个新的双靶分子文库 HAT和PDE5活性，2)阐明了我们新合成的化合物的药代动力学/药效学性质 体外和体内的双靶点分子，以及3)评估小鼠海马片的突触可塑性 来自用我们新合成的双靶点治疗的淀粉样蛋白沉积的转基因小鼠模型 配基。这些目标将通过药物化学方法的组合来实现，以产生 用于测试生物活性的新的化学实体以及生化和电生理技术 这些新的双靶分子在体外以及评估它们在体内的效果。来自这些的结果 实验将为治疗阿尔茨海默病的替代和新的治疗方法提供重要的见解 巧妙地调节两个已知在这种疾病的病因中发挥重要作用的分子靶点。

Alzheimer’s disease (AD) is a complex, multifactorial disease with a significant health and financial societal impact as there are no drugs that effectively counteract the disease. AD is characterized by impaired synaptic plasticity leading to defective hippocampal-dependent memory, which has been found to appear long before the buildup of amyloid plaques and neuronal cell death. This observation suggests that interventions targeting biological pathways that regulate synaptic plasticity may provide a way to slow down, arrest, and/or prevent the progression of neurodegenerative processes. The objective of this proposal is to identify first-in-class small molecules with dual target activity that enhance synaptic plasticity. In preliminary studies, we discovered that two distinct molecular targets, phosphodiesterase 5 (PDE5) and histone acetyltransferase (HAT) are crucial in synaptic plasticity. We developed small molecule PDE5 inhibitors and HAT activators that are able to rescue impaired synaptic plasticity in mouse hippocampal slices. In a proof-of-concept study, we demonstrated that a combination treatment with a PDE5 inhibitor and a HAT activator produces a 6-fold higher rescue of synaptic plasticity compared to treatment with the two compounds alone. These findings indicate that modulating these two targets involved in AD provides a more effective treatment than a single-target therapy. In this proposal, we plan to test the hypothesis that modulating PDE5 and HAT activity via a newly synthesized single molecule will result in a novel AD treatment. The multi-target directed ligand approach will be used to attain a PDE5 inhibitor/HAT activator drug molecule. This approach has emerged as a beneficial strategy for the treatment of complex diseases and presents several advantages with respect to combination therapy, including increased therapeutic efficacy, reduced drug-drug interactions, and simplified drug regimen. Specifically, we will test our hypothesis via the following specific aims: 1) design and synthesis of a library of new dual-target molecules with HAT and PDE5 activity, 2) elucidate the pharmacokinetic/pharmacodynamic properties of our newly synthesized dual-target molecules in vitro and in vivo, and 3) assess synaptic plasticity in mouse hippocampal slices derived from a genetically modified mouse model of amyloid deposition treated with our newly synthesized dual-target ligands. These aims will be addressed through a combination of medicinal chemistry approaches for generating new chemical entities, and biochemical and electrophysiological techniques for testing the biological activity of these new dual target molecules in vitro as well as assessing their in vivo efficacy. Results from these experiments will provide crucial insights into an alternative and novel therapeutic approach for treating AD based on cleverly modulating two molecular targets known to play a significant role in the etiopathology of this disease.