Faculty of Pharmacy, Jerash University, Al-Urdon St., Jerash 26150, Jordan.
Department of Basic Scientific Sciences, Faculty of Arts & Sciences, Applied Science Private University, Amman 11931, Jordan.
Molecules. 2022 Dec 12;27(24):8823. doi: 10.3390/molecules27248823.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common cause of dementia in the elderly. The complexity of AD has hindered the development of either a cure or a disease-modifying therapy to halt the disease progression. Numerous hypotheses were presented in order to explain the mechanisms underlying the pathogenesis of AD. Introduced in 1992, the "Amyloid Cascade Hypothesis" had a huge impact on the field and inspired the rise of various drug candidates, especially amyloid-beta (Aβ)-directed drugs; including beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors. Adopted by a number of pharmaceutical companies, the development of BACE1 inhibitors has gained momentum in the past decade with promising results from experimental and early clinical-phase studies. Nevertheless, nearly all BACE1 inhibitors failed in later phases of clinical trials, due to safety and/or efficacy issues, and others were discontinued early in favor of second-generation small-molecule candidates. This paper aims to provide a comprehensive review of all BACE1 inhibitors to ever reach clinical trials, and we discuss the challenges and different perspectives on whether BACE1 inhibitors are to be reconsidered or revitalized in the future.
阿尔茨海默病（AD）是最常见的神经退行性疾病，也是老年人痴呆症最常见的病因。AD 的复杂性阻碍了治愈或疾病修正疗法的发展，无法阻止疾病的进展。为了解释 AD 发病机制的机制，提出了许多假说。1992 年提出的“淀粉样蛋白级联假说”对该领域产生了巨大影响，并激发了各种药物候选物的出现，特别是针对淀粉样蛋白-β（Aβ）的药物；包括β-位点淀粉样前体蛋白裂解酶 1（BACE1）抑制剂。许多制药公司采用了 BACE1 抑制剂，在过去十年中，由于实验和早期临床阶段研究的结果令人鼓舞，该抑制剂的开发取得了进展。然而，由于安全性和/或疗效问题，几乎所有的 BACE1 抑制剂都在临床试验的后期阶段失败了，其他抑制剂也因第二代小分子候选药物而提前停止研发。本文旨在对所有进入临床试验的 BACE1 抑制剂进行全面综述，并讨论在未来是否应重新考虑或恢复使用 BACE1 抑制剂的挑战和不同观点。
