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Developments on BACE 1 Inhibitors as Anti‐Alzheimer Agents: A Perspective on Medicinal Chemistry‐Based Advances
Nemat Ali, Fahad T. Alotaibi, M. Arockia Babu, Takveer Singh, Yogita Tyagi, Abdullah N. Alotaibi, Nisha Bansal, Sarthak Puri. Archiv der Pharmazie, 2026-03-01
Topic: Amyloid, tau and blood-test diagnosis
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 (Aβ) 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 β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) plays a critical role in the generation of Aβ 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-generation 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-modifying therapies for AD treatment.
Key findings
- 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 β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) plays a critical role in the generation of Aβ peptides.
Why it matters
This review describes the role of BACE1 in generating Aβ peptides and the development of three generations of BACE1 inhibitors, noting that second-generation drugs failed in clinical trials due to adverse effects. It discusses third-generation compounds designed to balance efficacy, selectivity and safety, but no BACE1 inhibitor is presented as an established treatment for Alzheimer's disease.
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Study details
- Evidence strengthLow
How this study scored 33/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on senior author's track record, so that was left out: it earned 32 of the 96 points we could judge it on, which is 33 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Archiv der Pharmazie) |
| Journal's citation record | 1 / 4 | Archiv der Pharmazie: journal h-index 87 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 1 / 7 | Cited 1 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.5 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | 3 / 6 | Cited 4.2× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 1 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | — / 4 | OpenAlex's profile for last-listed author Sarthak Puri holds only 3 work(s), too few to judge a track record — left out of this score |
| Institution's track record | 0 / 3 | King Saud University: institution h-index 486 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41838033) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 32 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 32 of the 96 points we could judge it on is 33 out of 100. |
| Total | 33 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
May need a subscription OpenAlex found no free copy of the full text (checked 6 Feb 1020), so the publisher may charge for it. The PubMed abstract is free.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 8 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Ali, N., Alotaibi, F. T., Babu, M. A., Singh, T., Tyagi, Y., Alotaibi, A. N., et al. (2026). Developments on BACE 1 Inhibitors as Anti‐Alzheimer Agents: A Perspective on Medicinal Chemistry‐Based Advances. Archiv der Pharmazie. https://doi.org/10.1002/ardp.70220
Vancouver
Ali N, Alotaibi FT, Babu MA, Singh T, Tyagi Y, Alotaibi AN, et al. Developments on BACE 1 Inhibitors as Anti‐Alzheimer Agents: A Perspective on Medicinal Chemistry‐Based Advances. Archiv der Pharmazie. 2026. doi:10.1002/ardp.70220. PMID: 41838033.
BibTeX
@article{ali2026-41838033,
author = {Ali, Nemat and Alotaibi, Fahad T. and Babu, M. Arockia and Singh, Takveer and Tyagi, Yogita and Alotaibi, Abdullah N. and Bansal, Nisha and Puri, Sarthak},
title = {{Developments on BACE 1 Inhibitors as Anti‐Alzheimer Agents: A Perspective on Medicinal Chemistry‐Based Advances}},
journal = {Archiv der Pharmazie},
year = {2026},
doi = {10.1002/ardp.70220},
pmid = {41838033},
url = {https://doi.org/10.1002/ardp.70220}
}
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