{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T16:27:10Z","timestamp":1778084830127,"version":"3.51.4"},"reference-count":177,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"vor","delay-in-days":15,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Alzheimer's disease (AD) is a progressive and complicated neurodegenerative disorder that mostly affects the elderly and is characterized by memory loss, cognitive dysfunction, accumulation of amyloid beta (A\u03b2) plaques, neurofibrillary tangles, and cholinergic deficits. Current therapies used for AD, such as acetylcholinesterase inhibitors and NMDA receptor antagonist memantine, can only provide temporary or symptomatic relief, but they do not stop or reverse the progression of the disease. Numerous pathogenic hypotheses have been proposed to explain this mechanism; however, the amyloid cascade hypothesis remains the most widely accepted theory, as it suggests that \u03b2\u2010site amyloid precursor protein\u2010cleaving enzyme 1 (BACE1) plays a critical role in the generation of A\u03b2 peptides. Therefore, BACE1 may be a key therapeutic target. This review primarily focuses on the key role of BACE1 in AD pathogenesis and describes the development of its inhibitors over three generations, explaining their structure, design, and pharmacological properties. While the first generation lacked brain penetration, the second\u2010generation improved potency but encountered clinical trial failures due to adverse effects. The third generation of these drugs was designed to achieve a balance between efficacy, selectivity, and safety. Additionally, we review the promising molecules currently under clinical investigation, highlighting both their therapeutic potential and the challenges that remain in developing effective disease\u2010modifying therapies for AD treatment.<\/jats:p>","DOI":"10.1002\/ardp.70220","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T15:41:49Z","timestamp":1773675709000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Developments on BACE 1 Inhibitors as Anti\u2010Alzheimer Agents: A Perspective on Medicinal Chemistry\u2010Based Advances"],"prefix":"10.1002","volume":"359","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6525-4202","authenticated-orcid":false,"given":"Nemat","family":"Ali","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology College of Pharmacy, King Saud University Riyadh Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fahad T.","family":"Alotaibi","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Physiology, College of Medicine Imam Mohammad Ibn Saud Islamic University (IMSIU) Riyadh Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Arockia","family":"Babu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Medical and Allied Sciences Galgotias University Greater Noida Uttar Pradesh India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thakur Gurjeet","family":"Singh","sequence":"additional","affiliation":[{"name":"Centre of Research Impact and Outcome, Chitkara College of Pharmacy Chitkara University Rajpura Punjab India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yogita","family":"Tyagi","sequence":"additional","affiliation":[{"name":"Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University Premanagar Dehradun Uttarakhand India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdullah N.","family":"Alotaibi","sequence":"additional","affiliation":[{"name":"Department of Chemistry Imam Mohammad Ibn Saud Islamic University (IMSIU) Riyadh Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3190-0151","authenticated-orcid":false,"given":"Nisha","family":"Bansal","sequence":"additional","affiliation":[{"name":"Department of Biotechnology Graphic Era Deemed to be University Dehradun Uttarakhand India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2364-9985","authenticated-orcid":false,"given":"Sarthak","family":"Puri","sequence":"additional","affiliation":[{"name":"Goel Institute of Pharmacy and Sciences Lucknow Uttar Pradesh India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1132814"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200802808"},{"key":"e_1_2_10_4_1","volume-title":"The \u03b2\u2010Amyloid Hypothesis in Alzheimer's Disease: Seeing is Believing","author":"Kung H. 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