Department of Pharmaceutical Chemistry, Parul Institute of Pharmacy, Parul University, Vadodara, Gujarat, India.
Department of Pharmaceutical Chemistry, Parul Institute of Pharmacy, Parul University, Vadodara, Gujarat, India.
Bioorg Chem. 2024 Mar;144:107152. doi: 10.1016/j.bioorg.2024.107152. Epub 2024 Jan 27.
Alzheimer's disease (AD) is the most common form of dementia affecting specifically older population. AD is an irreversible neurodegenerative CNS disorder associated with complex pathophysiology. Presently, the USFDA has approved only four drugs viz. Donepezil, Rivastigmine, Memantine, and Galantamine for the treatment of AD. These drugs exhibit their neuroprotective effects either by inhibiting cholinesterase enzyme (ChE) or N-methyl-d-aspartate (NMDA) receptor. However, the conventional therapy "one target, one molecule" has failed to provide promising therapeutic effects due to the multifactorial nature of AD. This triggered the development of a novel strategy called Multi-Target Directed Ligand (MTDL) which involved designing one molecule that acts on multiple targets simultaneously. The present review discusses the detailed pathology involved in AD and the various MTDL design strategies bearing different heterocycles, in vitro and in vivo activities of the compounds, and their corresponding structure-activity relationships. This knowledge will allow us to identify and design more effective MTDLs for the treatment of AD.
阿尔茨海默病（AD）是最常见的痴呆症形式，主要影响老年人群。AD 是一种不可逆的神经退行性中枢神经系统疾病，与复杂的病理生理学有关。目前，美国食品和药物管理局（FDA）仅批准了四种药物用于 AD 的治疗，即多奈哌齐、利斯的明、美金刚和加兰他敏。这些药物通过抑制胆碱酯酶（ChE）或 N-甲基-D-天冬氨酸（NMDA）受体发挥其神经保护作用。然而，由于 AD 的多因素性质，传统的“一个靶点，一个分子”的治疗方法未能提供有希望的治疗效果。这促使人们开发了一种新的策略，称为多靶点定向配体（MTDL），该策略涉及设计一种同时作用于多个靶点的分子。本综述讨论了 AD 涉及的详细病理学以及带有不同杂环的各种 MTDL 设计策略、化合物的体外和体内活性及其相应的构效关系。这些知识将使我们能够识别和设计更有效的 MTDLs 来治疗 AD。
