{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T10:10:11Z","timestamp":1792404611102,"version":"4.4.0"},"reference-count":137,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T00:00:00Z","timestamp":1670803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Alzheimer\u2019s 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 \u201cAmyloid Cascade Hypothesis\u201d had a huge impact on the field and inspired the rise of various drug candidates, especially amyloid-beta (A\u03b2)-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.<\/jats:p>","DOI":"10.3390\/molecules27248823","type":"journal-article","created":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T03:32:32Z","timestamp":1670902352000},"page":"8823","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":109,"title":["BACE1 Inhibitors for Alzheimer\u2019s Disease: The Past, Present and Any Future?"],"prefix":"10.3390","volume":"27","author":[{"given":"Firas H.","family":"Bazzari","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, Jerash University, Al-Urdon St., Jerash 26150, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amjad H.","family":"Bazzari","sequence":"additional","affiliation":[{"name":"Department of Basic Scientific Sciences, Faculty of Arts & Sciences, Applied Science Private University, Amman 11931, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref_2","unstructured":"(2022, November 04). 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