Kadja Luana Chagas Monteiro, Marcone Gomes Dos Santos Alcântara, Nathalia Monteiro Lins Freire, Esaú Marques Brandão, Vanessa Lima do Nascimento, Líbni Maísa Dos Santos Viana, Thiago Mendonça de Aquino, Edeildo Ferreira da Silva-Júnior
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引用次数: 1
摘要
淀粉样蛋白-β (Aβ)的积累是与阿尔茨海默病(AD)进展相关的主要事件。多年来,已经报道了几种疾病调节方法,但没有临床成功。淀粉样蛋白级联假说提出了tau蛋白聚集和β-分泌酶(β-位点淀粉样蛋白前体蛋白切割酶1 - base -1)和γ-分泌酶蛋白酶的调节等重要靶点。BACE-1切割淀粉样蛋白前体蛋白(APP)以释放C99片段,在随后的γ分泌酶切割过程中产生几种Aβ肽。通过这种方式,BACE-1已成为药物化学中临床验证和有吸引力的靶标,因为它在a β生成速率中起着至关重要的作用。在这篇综述中,我们报告了候选药物在临床试验中的主要结果,如E2609、MK8931和AZD-3293,以及已经报道的抑制剂的药代动力学和药效学相关作用。考虑到它们的主要局限性和经验教训,展示了开发新的拟肽、非拟肽、自然发生和其他类抑制剂的现状。目标是提供一个广泛和完整的方法来研究这个问题,探索新的化学类别和观点。
The accumulation of amyloid-β (Aβ) is the main event related to Alzheimer's disease (AD) progression. Over the years, several disease-modulating approaches have been reported, but without clinical success. The amyloid cascade hypothesis evolved and proposed essential targets such as tau protein aggregation and modulation of β-secretase (β-site amyloid precursor protein cleaving enzyme 1 - BACE-1) and γ-secretase proteases. BACE-1 cuts the amyloid precursor protein (APP) to release the C99 fragment, giving rise to several Aβ peptide species during the subsequent γ-secretase cleavage. In this way, BACE-1 has emerged as a clinically validated and attractive target in medicinal chemistry, as it plays a crucial role in the rate of Aβ generation. In this review, we report the main results of candidates in clinical trials such as E2609, MK8931, and AZD-3293, in addition to highlighting the pharmacokinetic and pharmacodynamic-related effects of the inhibitors already reported. The current status of developing new peptidomimetic, non-peptidomimetic, naturally occurring, and other class inhibitors are demonstrated, considering their main limitations and lessons learned. The goal is to provide a broad and complete approach to the subject, exploring new chemical classes and perspectives.
期刊介绍:
Current Alzheimer Research publishes peer-reviewed frontier review, research, drug clinical trial studies and letter articles on all areas of Alzheimer’s disease. This multidisciplinary journal will help in understanding the neurobiology, genetics, pathogenesis, and treatment strategies of Alzheimer’s disease. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, molecular, and animal models. The journal also covers original articles on recent research in fast emerging areas of molecular diagnostics, brain imaging, drug development and discovery, and clinical aspects of Alzheimer’s disease. Manuscripts are encouraged that relate to the synergistic mechanism of Alzheimer''s disease with other dementia and neurodegenerative disorders. Book reviews, meeting reports and letters-to-the-editor are also published. The journal is essential reading for researchers, educators and physicians with interest in age-related dementia and Alzheimer’s disease. Current Alzheimer Research provides a comprehensive ''bird''s-eye view'' of the current state of Alzheimer''s research for neuroscientists, clinicians, health science planners, granting, caregivers and families of this devastating disease.