BACE1 Inhibitors: Design, Synthesis, Structure–Activity Relationships, and Therapeutic Applications in Alzheimer’s Disease and Beyond – An Updated Review

Amine Bayen; Mohamed Yafout; Mohamed El Bouamri; Amal Ait Haj Said; Adnane Benmoussa

doi:10.18596/jotcsa.1827742

BACE1 Inhibitors: Design, Synthesis, Structure–Activity Relationships, and Therapeutic Applications in Alzheimer’s Disease and Beyond – An Updated Review

Abstract

Beta secretase amyloid precursor protein–cleaving enzyme 1 (BACE1) initiates amyloid-β (Aβ) production, making it central to therapeutic strategies for Alzheimer’s disease (AD). Since its discovery, an extraordinary amount of effort has gone into designing molecules that safely and effectively inhibit its activity. Early peptidomimetic inhibitors taught us much about how BACE1 recognizes its substrates, but their large size and poor ability to enter the brain limited their therapeutic potential. Over time, medicinal chemistry shifted toward smaller, more drug-like scaffolds—including hydroxyethylamine, aminoimidazole, aminothiazoline, aminooxazoline, hydantoin, and dihydroquinazoline frameworks—guided by structural biology, fragment-based discovery, and increasingly sophisticated computational approaches. These refinements led to potent inhibitors with greatly improved pharmacokinetic profiles. Despite these advances, clinical outcomes have been disappointing. Several of the most promising candidates, such as verubecestat, atabecestat, lanabecestat, and elenbecestat, successfully lowered Aβ levels in humans yet failed to demonstrate clinical benefit and, in some cases, raised safety concerns. These setbacks underscored a crucial point: BACE1 participates in many physiological processes beyond APP cleavage. It also regulates pathways involved in myelination, synaptic function, neuronal development, and even systemic metabolism. As a result, chronic, full inhibition may have unintended biological consequences. This review brings together the major developments in BACE1 inhibitor design, highlighting how synthetic strategies and structure–activity relationships have evolved. It also discusses emerging therapeutic opportunities outside AD and reflects on why past clinical efforts fell short. Understanding these complexities is essential for shaping the next generation of safer, more targeted BACE1-modulating therapies.

Keywords

References

1. Rombouts FJR, Tresadern G, Delgado O, Martínez-Lamenca C, Van Gool M, García-Molina A, et al. 1,4-Oxazine β-secretase 1 (BACE1) inhibitors: From hit generation to orally bioavailable brain penetrant leads. J Med Chem [Internet]. 2015 Oct 22;58(20):8216–35. Available from: .
2. International AD, University M. World Alzheimer Report 2021: Journey through the diagnosis of dementia [Internet]. [cited 2025 Dec 27]. Available from: .
3. Ghosh AK, Gemma S. From traditional medicine to modern drugs: Historical perspective of structure‐based drug design. In: Structure‐Based Design of Drugs and Other Bioactive Molecules [Internet]. Wiley; 2014. p. 1–18. Available from: .
4. Jagtap AD, Kondekar NB, Hung PY, Hsieh CE, Yang CR, Chen GS, et al. 4-Substituted 2-amino-3,4-dihydroquinazolines with a 3-hairpin turn side chain as novel inhibitors of BACE-1. Bioorg Chem [Internet]. 2020 Jan;95:103135. Available from: .
5. Hardy JA, Higgins GA. Alzheimer’s disease: The amyloid cascade hypothesis. Science (80- ) [Internet]. 1992 Apr 10;256(5054):184–5. Available from: .
6. Thomas AA, Hunt KW, Newhouse B, Watts RJ, Liu X, Vigers G, et al. 8-Tetrahydropyran-2-yl chromans: Highly selective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors. J Med Chem [Internet]. 2014 Dec 11;57(23):10112–29. Available from: .
7. Liebsch F. Identification of novel molecular properties of the alzheimer disease beta-secretase (BACE1) and their functional consequences [Internet]. [Montreal,Quebec]: McGill University; 2017. Available from: .
8. Karch S, Broichhagen J, Schneider J, Böning D, Hartmann S, Schmid B, et al. A new fluorogenic small-molecule labeling tool for surface diffusion analysis and advanced fluorescence imaging of β-site amyloid precursor protein-cleaving enzyme 1 based on silicone rhodamine: SiR-BACE1. J Med Chem [Internet]. 2018 Jul 26;61(14):6121–39. Available from: .

9. Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, et al. Structure of the protease domain of memapsin 2 (β-secretase) complexed with inhibitor. Science (80- ) [Internet]. 2000 Oct 6;290(5489):150–3. Available from: .
10. Yan R, Vassar R. Targeting the β secretase BACE1 for alzheimer’s disease therapy. Lancet Neurol [Internet]. 2014 Mar 1;13(3):319–29. Available from: .
11. Ghosh AK, Osswald HL. BACE1 (β-secretase) inhibitors for the treatment of alzheimer’s disease. Chem Soc Rev [Internet]. 2014 Apr 2;43(19):6765–813. Available from: .
12. Johnson DS, Pettersson M. γ-Secretase modulators as Aβ42-lowering pharmacological agents to treat alzheimer’s disease. In 2017. p. 87–118. Available from: .
13. M Y, Shetty NS. Advances in the synthetic approaches to β-secretase (BACE-1) inhibitors in countering alzheimer’s: A comprehensive review. ACS Omega [Internet]. 2025 Aug 19;10(32):35367–433. Available from: .
14. Tarcsay Á, Keserű GM. Is there a link between selectivity and binding thermodynamics profiles? Drug Discov Today [Internet]. 2015 Jan;20(1):86–94. Available from: .
15. Sahlgren Bendtsen KM, Hall VJ. The breakthroughs and caveats of using human pluripotent stem cells in modeling alzheimer’s disease. Cells [Internet]. 2023 Jan 27;12(3):420. Available from: .
16. Egan MF, Kost J, Tariot PN, Aisen PS, Cummings JL, Vellas B, et al. Randomized trial of verubecestat for mild-to-moderate alzheimer’s disease. N Engl J Med [Internet]. 2018 May 3;378(18):1691–703. Available from: .
17. Henley D, Raghavan N, Sperling R, Aisen P, Raman R, Romano G. Preliminary results of a trial of atabecestat in preclinical alzheimer’s disease. N Engl J Med [Internet]. 2019 Apr 11;380(15):1483–5. Available from: .
18. Wessels AM, Tariot PN, Zimmer JA, Selzler KJ, Bragg SM, Andersen SW, et al. Efficacy and safety of lanabecestat for treatment of early and mild alzheimer disease. JAMA Neurol [Internet]. 2020 Feb 1;77(2):199. Available from: .
19. Kobayashi K, Taniguchi C, Tanaka M, Kimura R, Komurasaki K, Kuwano M, et al. Development of novel BACE1 inhibitors with a hydroxyproline-derived N-amidinopyrrolidine scaffold. Bioorg Med Chem [Internet]. 2025 Apr;120:118086. Available from: .
20. Bazzari FH, Bazzari AH. BACE1 inhibitors for alzheimer’s disease: The past, present and any future? Molecules [Internet]. 2022 Dec 12;27(24):8823. Available from: .
21. Coimbra JRM, Marques DFF, Baptista SJ, Pereira CMF, Moreira PI, Dinis TCP, et al. Highlights in BACE1 inhibitors for alzheimer’s disease treatment. Front Chem [Internet]. 2018 May 24;6:178. Available from: .
22. Koriyama Y, Hori A, Ito H, Yonezawa S, Baba Y, Tanimoto N, et al. Discovery of atabecestat (JNJ-54861911): A thiazine-based β-amyloid precursor protein cleaving enzyme 1 inhibitor advanced to the phase 2b/3 EARLY clinical trial. J Med Chem [Internet]. 2021 Feb 25;64(4):1873–88. Available from: .
23. Zhang Z, Huang J, Shen Y, Li R. BACE1-Dependent neuregulin-1 signaling: An implication for schizophrenia. Front Mol Neurosci [Internet]. 2017 Sep 25;10:302. Available from: .
24. Pigoni M, Gunnersen JM, Lichtenthaler SF. Seizure-6 proteins highlight BACE1 functions in neurobiology. Oncotarget [Internet]. 2017 Jan 31;8(5):7214–5. Available from: .
25. Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci [Internet]. 2006 Dec 12;9(12):1520–5. Available from: .
26. Wang NL. Neurodegeneration in diabetic retinopathy. Chin Med J (Engl) [Internet]. 2016 Dec 20;129(24):3001–3. Available from: .
27. Butini S, Brogi S, Novellino E, Campiani G, Ghosh A, Brindisi M, et al. The structural evolution of β-secretase inhibitors: A focus on the development of small-molecule inhibitors. Curr Top Med Chem [Internet]. 2013 Jul 31;13(15):1787–807. Available from: .
28. Lin T, Liang T, Shen Y, Gao F. BACE1 inhibition protects against type 2 diabetes mellitus by restoring insulin receptor in mice. Int J Mol Sci [Internet]. 2025 May 26;26(11):5100. Available from: .
29. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, et al. β-secretase cleavage of alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science (80- ) [Internet]. 1999 Oct 22;286(5440):735–41. Available from: .
30. Ghosh AK, Shin D, Debbie Downs, Koelsch G, Lin X, Ermolieff J, et al. Design of potent inhibitors for human brain memapsin 2 (β-secretase). J Am Chem Soc [Internet]. 2000 Apr 1;122(14):3522–3. Available from: .
31. Arya R, Jain S, Paliwal S, Madan K, Sharma S, Mishra A, et al. BACE1 inhibitors: A promising therapeutic approach for the management of alzheimer’s disease. Asian Pac J Trop Biomed [Internet]. 2024 Sep;14(9):369–81. Available from: .
32. Amini R, Moradi S, Najafi R, Mazdeh M, Taherkhani A. BACE1 inhibition utilizing organic compounds holds promise as a potential treatment for alzheimer’s and parkinson’s diseases. Moreno S, editor. Oxid Med Cell Longev [Internet]. 2024 Feb 22;2024:654606. Available from: .
33. Estrada Valencia MH. Exploring the N-Benzylpiperidine and N, N-Dibenzyl(N-Methyl)amine fragments as privileged structures in the search of new multitarget directed drugs for alzheimer’s disease [Internet]. [Madrid]: Departamento de Química Orgánica y Farmacéutica; 2017. Available from: .
34. Naushad M, Durairajan SSK, Bera AK, Senapati S, Li M. Natural compounds with anti-BACE1 activity as promising therapeutic drugs for treating alzheimerʼs disease. Planta Med [Internet]. 2019 Nov 16;85(17):1316–25. Available from: .
35. Gudoityte E, Arandarcikaite O, Mazeikiene I, Bendokas V, Liobikas J. Ursolic and oleanolic acids: Plant metabolites with neuroprotective potential. Int J Mol Sci [Internet]. 2021 Apr 27;22(9):4599. Available from: .
36. Ribaudo G, Coghi P, Zanforlin E, Law BYK, Wu YYJ, Han Y, et al. Semi-synthetic isoflavones as BACE-1 inhibitors against alzheimer’s disease. Bioorg Chem [Internet]. 2019 Jun;87:474–83. Available from: .
37. Jannat S, Balupuri A, Ali MY, Hong SS, Choi CW, Choi YH, et al. Inhibition of β-site amyloid precursor protein cleaving enzyme 1 and cholinesterases by pterosins via a specific structure−activity relationship with a strong BBB permeability. Exp Mol Med [Internet]. 2019 Feb 12;51(2):1–18. Available from: .
38. Rosales Hernández MC, Olvera-Valdez M, Velazquez Toledano J, Mendieta Wejebe JE, Fragoso Morales LG, Cruz A. Exploring the benzazoles derivatives as pharmacophores for AChE, BACE1, and as anti-Aβ aggregation to find multitarget compounds against alzheimer’s disease. Molecules [Internet]. 2024 Oct 9;29(19):4780. Available from: .
39. Baiseitova A, Shah AB, Kim JY, Ban YJ, Kim JH, Nafiah MA, et al. O-alkylated quercetins with selective acetylcholinesterase and β-secretase inhibitions from Melicope glabra leaves, and their flavonols profile by LC-ESI-Q-TOF/MS. J Funct Foods [Internet]. 2021 Sep;84:104602. Available from: .
40. Panyatip P, Tadtong S, Sousa E, Puthongking P. BACE1 inhibitor, neuroprotective, and neuritogenic activities of melatonin derivatives. Sci Pharm [Internet]. 2020 Dec 4;88(4):58. Available from: .
41. Gaba S, Saini A, Singh G, Monga V. An insight into the medicinal attributes of berberine derivatives: A review. Bioorg Med Chem [Internet]. 2021 May;38:116143. Available from: .
42. Kulshreshtha A, Piplani P. Current pharmacotherapy and putative disease-modifying therapy for alzheimer’s disease. Neurol Sci [Internet]. 2016 Sep 1;37(9):1403–35. Available from: .
43. Hu J, Cwi CL, Smiley DL, Timm D, Erickson JA, McGee JE, et al. Design and synthesis of statine-containing BACE inhibitors. Bioorg Med Chem Lett [Internet]. 2003 Dec;13(24):4335–9. Available from: .
44. Kimura T, Shuto D, Hamada Y, Igawa N, Kasai S, Liu P, et al. Design and synthesis of highly active alzheimer’s β-secretase (BACE1) inhibitors, KMI-420 and KMI-429, with enhanced chemical stability. Bioorg Med Chem Lett [Internet]. 2005 Jan;15(1):211–5. Available from: .
45. Hamada Y, Igawa N, Ikari H, Ziora Z, Nguyen JT, Yamani A, et al. β-Secretase inhibitors: Modification at the P4 position and improvement of inhibitory activity in cultured cells. Bioorg Med Chem Lett [Internet]. 2006 Aug;16(16):4354–9. Available from: .
46. Hamada Y, Ohta H, Miyamoto N, Yamaguchi R, Yamani A, Hidaka K, et al. Novel non-peptidic and small-sized BACE1 inhibitors. Bioorg Med Chem Lett [Internet]. 2008 Mar;18(5):1654–8. Available from: .
47. Maillard MC, Hom RK, Benson TE, Moon JB, Mamo S, Bienkowski M, et al. Design, synthesis, and crystal structure of hydroxyethyl secondary amine-based peptidomimetic inhibitors of human β-secretase. J Med Chem [Internet]. 2007 Feb 1;50(4):776–81. Available from: .
48. Freskos JN, Fobian YM, Benson TE, Moon JB, Bienkowski MJ, Brown DL, et al. Design of potent inhibitors of human β-secretase. Part 2. Bioorg Med Chem Lett [Internet]. 2007 Jan;17(1):78–81. Available from: .
49. Beswick P, Charrier N, Clarke B, Demont E, Dingwall C, Dunsdon R, et al. BACE-1 inhibitors part 3: Identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells. Bioorg Med Chem Lett [Internet]. 2008 Feb;18(3):1022–6. Available from: .
50. Clarke B, Demont E, Dingwall C, Dunsdon R, Faller A, Hawkins J, et al. BACE-1 inhibitors part 2: Identification of hydroxy ethylamines (HEAs) with reduced peptidic character. Bioorg Med Chem Lett [Internet]. 2008 Feb;18(3):1017–21. Available from: .
51. Charrier N, Clarke B, Cutler L, Demont E, Dingwall C, Dunsdon R, et al. Second generation of hydroxyethylamine BACE-1 inhibitors: Optimizing potency and oral bioavailability. J Med Chem [Internet]. 2008 Jun 1;51(11):3313–7. Available from: .
52. Ghosh AK, Kumaragurubaran N, Hong L, Kulkarni S, Xu X, Miller HB, et al. Potent memapsin 2 (β-secretase) inhibitors: Design, synthesis, protein-ligand X-ray structure, and in vivo evaluation. Bioorg Med Chem Lett [Internet]. 2008 Feb;18(3):1031–6. Available from: .
53. Chang W, Huang X, Downs D, Cirrito JR, Koelsch G, Holtzman DM, et al. β‐Secretase inhibitor GRL‐8234 rescues age‐related cognitive decline in APP transgenic mice. FASEB J [Internet]. 2011 Feb 8;25(2):775–84. Available from: .
54. Iserloh U, Wu Y, Cumming JN, Pan J, Wang LY, Stamford AW, et al. Potent pyrrolidine- and piperidine-based BACE-1 inhibitors. Bioorg Med Chem Lett [Internet]. 2008 Jan;18(1):414–7. Available from: .
55. Iserloh U, Pan J, Stamford AW, Kennedy ME, Zhang Q, Zhang L, et al. Discovery of an orally efficaceous 4-phenoxypyrrolidine-based BACE-1 inhibitor. Bioorg Med Chem Lett [Internet]. 2008 Jan;18(1):418–22. Available from: .
56. Cumming JN, Le TX, Babu S, Carroll C, Chen X, Favreau L, et al. Rational design of novel, potent piperazinone and imidazolidinone BACE1 inhibitors. Bioorg Med Chem Lett [Internet]. 2008 Jun;18(11):3236–41. Available from: .
57. Cumming J, Babu S, Huang Y, Carrol C, Chen X, Favreau L, et al. Piperazine sulfonamide BACE1 inhibitors: Design, synthesis, and in vivo characterization. Bioorg Med Chem Lett [Internet]. 2010 May;20(9):2837–42. Available from: .
58. Thompson LA, Shi J, Decicco CP, Tebben AJ, Olson RE, Boy KM, et al. Synthesis and in vivo evaluation of cyclic diaminopropane BACE-1 inhibitors. Bioorg Med Chem Lett [Internet]. 2011 Nov 15;21(22):6909–15. Available from: .
59. Rueeger H, Rondeau JM, McCarthy C, Möbitz H, Tintelnot-Blomley M, Neumann U, et al. Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors. Bioorg Med Chem Lett [Internet]. 2011 Apr 1;21(7):1942–7. Available from: .
60. Coburn CA, Stachel SJ, Jones KG, Steele TG, Rush DM, DiMuzio J, et al. BACE-1 inhibition by a series of ψ[CH2NH] reduced amide isosteres. Bioorg Med Chem Lett [Internet]. 2006 Jul 15;16(14):3635–8. Available from: .
61. Rajapakse HA, Nantermet PG, Selnick HG, Munshi S, McGaughey GB, Lindsley SR, et al. Discovery of oxadiazoyl tertiary carbinamine inhibitors of β-secretase (BACE-1). J Med Chem [Internet]. 2006 Dec 1;49(25):7270–3. Available from: .
62. Stauffer SR, Stanton MG, Gregro AR, Steinbeiser MA, Shaffer JR, Nantermet PG, et al. Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind β-secretase in a N-terminal 10s-loop down conformation. Bioorg Med Chem Lett [Internet]. 2007 Mar 15;17(6):1788–92. Available from: .
63. Stanton MG, Stauffer SR, Gregro AR, Steinbeiser M, Nantermet P, Sankaranarayanan S, et al. Discovery of isonicotinamide derived β-secretase inhibitors: In Vivo reduction of β-amyloid. J Med Chem [Internet]. 2007 Jul 1;50(15):3431–3. Available from: .
64. Nantermet PG, Rajapakse HA, Stanton MG, Stauffer SR, Barrow JC, Gregro AR, et al. Evolution of tertiary carbinamine BACE‐1 inhibitors: Aβ reduction in rhesus CSF upon oral dosing. ChemMedChem [Internet]. 2009 Jan 12;4(1):37–40. Available from: .
65. Sankaranarayanan S, Holahan MA, Colussi D, Crouthamel MC, Devanarayan V, Ellis J, et al. First demonstration of cerebrospinal fluid and plasma Aβ lowering with oral administration of a β-site amyloid precursor protein-cleaving enzyme 1 inhibitor in nonhuman primates. J Pharmacol Exp Ther [Internet]. 2009 Jan 1;328(1):131–40. Available from: .
66. Zhu H, Young MB, Nantermet PG, Graham SL, Colussi D, Lai MT, et al. Rapid P1 SAR of brain penetrant tertiary carbinamine derived BACE inhibitors. Bioorg Med Chem Lett [Internet]. 2010 Mar 1;20(5):1779–82. Available from: .
67. Monceaux CJ, Hirata-Fukae C, Lam PCH, Totrov MM, Matsuoka Y, Carlier PR. Triazole-linked reduced amide isosteres: An approach for the fragment-based drug discovery of anti-alzheimer’s BACE1 inhibitors. Bioorg Med Chem Lett [Internet]. 2011 Jul 1;21(13):3992–6. Available from: .
68. Ghosh AK, Venkateswara Rao K, Yadav ND, Anderson DD, Gavande N, Huang X, et al. Structure-based design of highly selective β-secretase inhibitors: Synthesis, biological evaluation, and protein–ligand X-ray crystal structure. J Med Chem [Internet]. 2012 Nov 8;55(21):9195–207. Available from: .
69. Liu JK, Gu W, Cheng XR, Cheng JP, Zhou WX, Nie AH. Design and synthesis of cyclic acylguanidines as BACE1 inhibitors. Chinese Chem Lett [Internet]. 2015 Oct 1;26(10):1327–30. Available from: .
70. Cole DC, Manas ES, Stock JR, Condon JS, Jennings LD, Aulabaugh A, et al. Acylguanidines as small-molecule β-secretase inhibitors. J Med Chem [Internet]. 2006 Oct 1;49(21):6158–61. Available from: .
71. Jennings LD, Cole DC, Stock JR, Sukhdeo MN, Ellingboe JW, Cowling R, et al. Acylguanidine inhibitors of β-secretase: Optimization of the pyrrole ring substituents extending into the S’1 substrate binding pocket. Bioorg Med Chem Lett [Internet]. 2008 Jan 15;18(2):767–71. Available from: .
72. Gerritz SW, Zhai W, Shi S, Zhu S, Toyn JH, Meredith JE, et al. Acyl guanidine inhibitors of β-secretase (BACE-1): Optimization of a micromolar hit to a nanomolar lead via iterative solid- and solution-phase library synthesis. J Med Chem [Internet]. 2012 Nov 8;55(21):9208–23. Available from: .
73. Murray CW, Callaghan O, Chessari G, Cleasby A, Congreve M, Frederickson M, et al. Application of fragment screening by X-ray crystallography to β-secretase. J Med Chem [Internet]. 2007 Mar 1;50(6):1116–23. Available from: .
74. Congreve M, Aharony D, Albert J, Callaghan O, Campbell J, Carr RAE, et al. Application of fragment screening by X-ray crystallography to the discovery of aminopyridines as inhibitors of β-secretase. J Med Chem [Internet]. 2007 Mar 1;50(6):1124–32. Available from: .
75. Hilpert H, Guba W, Woltering TJ, Wostl W, Pinard E, Mauser H, et al. β-secretase (BACE1) inhibitors with high in vivo efficacy suitable for clinical evaluation in alzheimer’s disease. J Med Chem [Internet]. 2013 May 23;56(10):3980–95. Available from: .
76. Konno H, Sato T, Saito Y, Sakamoto I, Akaji K. Synthesis and evaluation of aminopyridine derivatives as potential BACE1 inhibitors. Bioorg Med Chem Lett [Internet]. 2015 Nov 15;25(22):5127–32. Available from: .
77. Bhatia S, Singh M, Sharma P, Mujwar S, Singh V, Mishra KK, et al. Scaffold morphing and in silico design of potential BACE-1 (β-secretase) inhibitors: A hope for a newer dawn in anti-alzheimer therapeutics. Molecules [Internet]. 2023 Aug 12;28(16):6032. Available from: .
78. Malamas MS, Erdei J, Gunawan I, Barnes K, Johnson M, Hui Y, et al. Aminoimidazoles as potent and selective human β-secretase (BACE1) inhibitors. J Med Chem [Internet]. 2009 Oct 22;52(20):6314–23. Available from: .
79. Yin G, Ma J, Shi H, Tao Q. Facile one-pot procedure for the synthesis of 2-aminothiazole derivatives. Heterocycles [Internet]. 2012;85(8):1941. Available from: .
80. Maia MA, Sousa E. BACE-1 and γ-secretase as therapeutic targets for alzheimer’s disease. Pharmaceuticals [Internet]. 2019 Mar 19;12(1):41. Available from: .
81. Patel S, Bansoad AV, Singh R, Khatik GL. BACE1: A key regulator in alzheimer’s disease progression and current development of its inhibitors. Curr Neuropharmacol [Internet]. 2022 Jun;20(6):1174–93. Available from: .
82. Arbel M, Solomon B. A novel immunotherapy for alzheimers disease: Antibodies against the β-secretase cleavage site of APP. Curr Alzheimer Res [Internet]. 2007 Sep 1;4(4):437–45. Available from: .
83. Epstein O, Bryan MC, Cheng AC, Derakhchan K, Dineen TA, Hickman D, et al. Lead optimization and modulation of hERG activity in a series of aminooxazoline xanthene β-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors. J Med Chem [Internet]. 2014 Dec 11;57(23):9796–810. Available from: .
84. Huang H, La DS, Cheng AC, Whittington DA, Patel VF, Chen K, et al. Structure- and property-based design of aminooxazoline xanthenes as selective, orally efficacious, and CNS penetrable BACE inhibitors for the treatment of alzheimer’s disease. J Med Chem [Internet]. 2012 Nov 8;55(21):9156–69. Available from: .
85. Low JD, Bartberger MD, Chen K, Cheng Y, Fielden MR, Gore V, et al. Development of 2-aminooxazoline 3-azaxanthene β-amyloid cleaving enzyme (BACE) inhibitors with improved selectivity against Cathepsin D. Medchemcomm [Internet]. 2017 Jun 21;8(6):1196–206. Available from: .
86. Kumar V. Designedsynthesis of diversely substituted hydantoins and hydantoin-based hybrid molecules: A personal account. Synlett [Internet]. 2021 Dec 12;32(19):1897–910. Available from: .
87. Malamas MS, Barnes K, Johnson M, Hui Y, Zhou P, Turner J, et al. Di-substituted pyridinyl aminohydantoins as potent and highly selective human β-secretase (BACE1) inhibitors. Bioorg Med Chem [Internet]. 2010 Jan 15;18(2):630–9. Available from: .
88. Zhou P, Li Y, Fan Y, Wang Z, Chopra R, Olland A, et al. Pyridinyl aminohydantoins as small molecule BACE1 inhibitors. Bioorg Med Chem Lett [Internet]. 2010 Apr 1;20(7):2326–9. Available from: .
89. Egbertson M, McGaughey GB, Pitzenberger SM, Stauffer SR, Coburn CA, Stachel SJ, et al. Methyl-substitution of an iminohydantoin spiropiperidine β-secretase (BACE-1) inhibitor has a profound effect on its potency. Bioorg Med Chem Lett [Internet]. 2015 Nov 1;25(21):4812–9. Available from: .
90. Fan TY, Wu WY, Yu SP, Zhong Y, Zhao C, Chen M, et al. Design, synthesis and evaluation of 2-amino-imidazol-4-one derivatives as potent β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) inhibitors. Bioorg Med Chem Lett [Internet]. 2019 Dec 15;29(24):126772. Available from: .
91. Cumming JN, Smith EM, Wang L, Misiaszek J, Durkin J, Pan J, et al. Structure based design of iminohydantoin BACE1 inhibitors: Identification of an orally available, centrally active BACE1 inhibitor. Bioorg Med Chem Lett [Internet]. 2012 Apr 1;22(7):2444–9. Available from: .
92. Malamas MS, Erdei J, Gunawan I, Barnes K, Hui Y, Johnson M, et al. New pyrazolyl and thienyl aminohydantoins as potent BACE1 inhibitors: Exploring the S2′ region. Bioorg Med Chem Lett [Internet]. 2011 Sep 15;21(18):5164–70. Available from: .
93. Ghosh AK, Pandey S, Gangarajula S, Kulkarni S, Xu X, Rao KV, et al. Structure-based design, synthesis, and biological evaluation of dihydroquinazoline-derived potent β-secretase inhibitors. Bioorg Med Chem Lett [Internet]. 2012 Sep;22(17):5460–5. Available from: .
94. Küçükoğlu K, Özdemir A. BACE-1 enzyme: A promising target for alzheimer’s disease. Int J Innov Res Rev [Internet]. 2025;9(1):1–21. Available from: .
95. Cheng Y, Judd TC, Bartberger MD, Brown J, Chen K, Fremeau RT, et al. From fragment screening to in vivo efficacy: Optimization of a series of 2-Aminoquinolines as potent inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). J Med Chem [Internet]. 2011 Aug 25;54(16):5836–57. Available from: .
96. Matošević A, Bartolić M, Maraković N, Zandona A, Petrić R, Opsenica D, et al. Synthesis and biological evaluation of novel aminoquinolines with an n-octyl linker: Impact of halogen substituents on C(7) or a terminal amino group on anticholinesterase and BACE1 activity. Bioorg Med Chem Lett [Internet]. 2024 Nov;112:129928. Available from: .
97. Ghosh AK. BACE1 inhibitor drugs for the treatment of Alzheimer’s disease: Lessons learned, challenges to overcome, and future prospects. Glob Heal Med [Internet]. 2024 Jun 30;6(3):164–9. Available from: .
98. Ravi A, AlKubaisi BO, Srikanth G, Menon V, Ramadan WS, El-Awady R, et al. Discovery of novel imidazolyl-6,7-dimethoxyisoquinoline derivatives as promising BACE1 inhibitors for management of Alzheimer’s disease. J Mol Struct [Internet]. 2025 Apr;1328:141275. Available from: .
99. Zhao J, Liu X, Xia W, Zhang Y, Wang C. Targeting amyloidogenic processing of APP in alzheimer’s disease. Front Mol Neurosci [Internet]. 2020 Aug 4;13. Available from: .
100. LY2886721 | ALZFORUM [Internet]. [cited 2025 Nov 10]. Available from: .
101. Reising NC, Day TA, Hole JT, Tingley FD, Gonzalez-DeWhitt PA, Mergott DJ, et al. Measurement of endogenous mouse tau in cerebrospinal fluid from aged pdapp mice following treatment with Ab-lowering compounds. Alzheimer’s Dement [Internet]. 2018 Jul;14(7S_Part_5):P314. Available from: .
102. Martenyi F, Dean RA, Lowe S, Nakano M, Monk S, Willis BA, et al. BACE inhibitor LY2886721 safety and central and peripheral PK and PD in healthy subjects (HSs). Alzheimer’s Dement [Internet]. 2012 Jul;8(4S_Part_16):P583–4. Available from: .
103. Dong Y, Li X, Cheng J, Hou L. Drug development for alzheimer’s disease: Microglia induced neuroinflammation as a target? Int J Mol Sci [Internet]. 2019 Jan 28;20(3):558. Available from: .
104. May PC, Willis BA, Lowe SL, Dean RA, Monk SA, Cocke PJ, et al. The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans. J Neurosci [Internet]. 2015 Jan 21;35(3):1199–210. Available from: .
105. Dekeryte R, Franklin Z, Hull C, Croce L, Kamli-Salino S, Helk O, et al. The BACE1 inhibitor LY2886721 improves diabetic phenotypes of BACE1 knock-in mice. Biochim Biophys Acta - Mol Basis Dis [Internet]. 2021 Jul;1867(7):166149. Available from: .
106. Verubecestat | ALZFORUM [Internet]. [cited 2025 Nov 10]. Available from: .
107. Chris Min K, Dockendorf MF, Palcza J, Tseng J, Ma L, Stone JA, et al. Pharmacokinetics and pharmacodynamics of the BACE1 inhibitor verubecestat (MK‐8931) in healthy Japanese adults: A randomized, placebo‐controlled study. Clin Pharmacol Ther [Internet]. 2019 May 18;105(5):1234–43. Available from: .
108. Sergott RC, Raji A, Kost J, Sur C, Jackson S, Locco A, et al. Retinal Optical Coherence Tomography Metrics Are Unchanged in Verubecestat Alzheimer’s Disease Clinical Trial but Correlate with Baseline Regional Brain Atrophy. Subramanian M, editor. J Alzheimer’s Dis [Internet]. 2021 Jan 5;79(1):275–87. Available from: .
109. Gharat R, Dixit G, Khambete M, Prabhu A. Targets, trials and tribulations in alzheimer therapeutics. Eur J Pharmacol [Internet]. 2024 Jan;962:176230. Available from: .
110. Moriyama T, Fukushima T, Kokate T, Albala B. Preclinical studies with elenbecestat, a novel bace1 inhibitor, show no evidence of hypopigmentation. Alzheimer’s Dement [Internet]. 2017 Jul 1;13(7S_Part_19):P944–P944. Available from: .
111. Lynch SY, Kaplow J, Zhao J, Dhadda S, Luthman J, Albala B. Elenbecestat, e2609, A bace inhibitor: Results from a phase-2 study in subjects with mild cognitive impairment and mild-to-moderate dementia due to alzheimer’s disease. Alzheimer’s Dement [Internet]. 2018 Jul 1;14(7S_Part_31):P1623–P1623. Available from: .
112. NCT03036280: A trial that was reported late by Eisai Co., Ltd. A Placebo-Controlled, Double-Blind, Parallel-Group, 24-Month Study With an Open-Label Extension Phase to Evaluate the Efficacy and Safety of Elenbecestat (E2609) in Subjects With Early Alzheimer’s Disease [Internet]. [cited 2025 Nov 10]. Available from: .
113. Das B, Yan R. A close look at BACE1 inhibitors for alzheimer’s disease treatment. CNS Drugs [Internet]. 2019 Mar 4;33(3):251–63. Available from: .
114. Plucińska K, Dekeryte R, Koss D, Shearer K, Mody N, Whitfield PD, et al. Neuronal human BACE1 knockin induces systemic diabetes in mice. Diabetologia [Internet]. 2016 Jul 2;59(7):1513–23. Available from: .
115. Bao H, Shen Y. Unmasking BACE1 in aging and age-related diseases. Trends Mol Med [Internet]. 2023 Feb 1;29(2):99–111. Available from: .
116. Sayad A, Najafi S, Hussen BM, Abdullah ST, Movahedpour A, Taheri M, et al. The emerging roles of the β-secretase BACE1 and the long non-coding RNA BACE1-AS in human diseases: A focus on neurodegenerative diseases and cancer. Front Aging Neurosci [Internet]. 2022 Mar 21;14:853180. Available from: .
117. Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, et al. Control of peripheral nerve myelination by the ß-secretase BACE1. Science (80- ) [Internet]. 2006 Oct 27;314(5799):664–6. Available from: .
118. Fleck D, van Bebber F, Colombo A, Galante C, Schwenk BM, Rabe L, et al. Dual cleavage of neuregulin 1 type III by BACE1 and ADAM17 liberates its EGF-like domain and allows paracrine signaling. J Neurosci [Internet]. 2013 May 1;33(18):7856–69. Available from: .
119. Hu X, Hu J, Dai L, Trapp B, Yan R. Axonal and schwann Cell BACE1 is equally required for remyelination of peripheral nerves. J Neurosci [Internet]. 2015 Mar 4;35(9):3806–14. Available from: .
120. Cheret C, Willem M, Fricker FR, Wende H, Wulf-Goldenberg A, Tahirovic S, et al. Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles. EMBO J [Internet]. 2013 Jun 21;32(14):2015–28. Available from: .
121. Koelsch G. BACE1 function and inhibition: Implications of intervention in the amyloid pathway of alzheimer’s disease pathology. Molecules [Internet]. 2017 Oct 13;22(10):1723. Available from: .
122. Zhai K, Huang Z, Huang Q, Tao W, Fang X, Zhang A, et al. Pharmacological inhibition of BACE1 suppresses glioblastoma growth by stimulating macrophage phagocytosis of tumor cells. Nat Cancer [Internet]. 2021 Nov 8;2(11):1136–51. Available from: .
123. Farris F, Matafora V, Bachi A. The emerging role of β-secretases in cancer. J Exp Clin Cancer Res [Internet]. 2021 Apr 29;40(1):147. Available from: .
124. Rather HA, Almousa S, Kumar A, Sharma M, Pennington I, Kim S, et al. The β-secretase 1 enzyme as a novel therapeutic target for prostate cancer. Cancers (Basel) [Internet]. 2023 Dec 19;16(1):10. Available from: .
125. Müller SA, Shmueli MD, Feng X, Tüshaus J, Schumacher N, Clark R, et al. The alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130. Mol Neurodegener [Internet]. 2023 Feb 21;18(1):13. Available from: .
126. Chen L, Huang Y, Guo J, Li Y. Expression of Bace1 is positive with the progress of atherosclerosis and formation of foam cell. Biochem Biophys Res Commun [Internet]. 2020 Jul;528(3):440–6. Available from: .
127. Katusic ZS. Vascular endothelial dysfunction: Does tetrahydrobiopterin play a role? Am J Physiol Circ Physiol [Internet]. 2001 Sep 1;281(3):H981–6. Available from: .
128. He T, d’Uscio L V, Sun R, Santhanam AVR, Katusic ZS. Inactivation of BACE1 increases expression of endothelial nitric oxide synthase in cerebrovascular endothelium. J Cereb Blood Flow Metab [Internet]. 2022 Oct 8;42(10):1920–32. Available from: .
129. Bampatsias D, Mavroeidis I, Tual-Chalot S, Vlachogiannis NI, Bonini F, Sachse M, et al. Beta-secretase-1 antisense RNA Is associated with vascular ageing and atherosclerotic cardiovascular disease. Thromb Haemost [Internet]. 2022 Nov 1;122(11):1932–42. Available from: .
130. Katusic ZS, d’Uscio L V., He T. Cerebrovascular endothelial dysfunction: Role of BACE1. Arterioscler Thromb Vasc Biol [Internet]. 2024 Aug;44(8):1737–47. Available from: .
131. Taylor HA, Przemylska L, Clavane EM, Meakin PJ. BACE1: More than just a β‐secretase. Obes Rev [Internet]. 2022 Jul 4;23(7):e13430. Available from: .
132. Hessler S, Zheng F, Hartmann S, Rittger A, Lehnert S, Völkel M, et al. β-secretase BACE1 regulates hippocampal and reconstituted M-currents in a β-subunit-like fashion. J Neurosci [Internet]. 2015 Feb 25;35(8):3298–311. Available from: .
133. Lehnert S, Hartmann S, Hessler S, Adelsberger H, Huth T, Alzheimer C. Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond alzheimer’s disease. Channels [Internet]. 2016 Sep 2;10(5):365–78. Available from: .
134. Ou-Yang MH, Kurz JE, Nomura T, Popovic J, Rajapaksha TW, Dong H, et al. Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice. Sci Transl Med [Internet]. 2018 Sep 19;10(459):eaao5620. Available from: .
135. Hitt BD, Jaramillo TC, Chetkovich DM, Vassar R. BACE1-/- mice exhibit seizure activity that does not correlate with sodium channel level or axonal localization. Mol Neurodegener [Internet]. 2010 Dec 23;5(1):31. Available from: .
136. Munro KM, Nash A, Pigoni M, Lichtenthaler SF, Gunnersen JM. Functions of the alzheimer’s disease protease BACE1 at the synapse in the central nervous system. J Mol Neurosci [Internet]. 2016 Nov 25;60(3):305–15. Available from: .
137. Filser S, Ovsepian S V., Masana M, Blazquez‐Llorca L, Brandt Elvang A, Volbracht C, et al. Pharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions. Biol Psychiatry [Internet]. 2015 Apr;77(8):729–39. Available from: .
138. Savonenko A V., Melnikova T, Laird FM, Stewart KA, Price DL, Wong PC. Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice. Proc Natl Acad Sci [Internet]. 2008 Apr 8;105(14):5585–90. Available from: .

Details

Primary Language

English

Subjects

Forensic Chemistry, Proteins and Peptides, Medicinal and Biomolecular Chemistry (Other)

Journal Section

Review

Authors

Amine Bayen ^*
0009-0002-4601-3547
Morocco

Mohamed Yafout
0000-0002-8936-8092
Morocco

Mohamed El Bouamri
0009-0002-6553-3740
Morocco

Amal Ait Haj Said
0000-0003-4996-8410
Morocco

Adnane Benmoussa
0000-0002-1037-7819
Morocco

Publication Date

May 17, 2026

Submission Date

November 21, 2025

Acceptance Date

April 13, 2026

Published in Issue

Year 2026 Number: 2026-1

DOI

https://doi.org/10.18596/jotcsa.1827742

IZ

https://izlik.org/JA65UD64KH

Cite

RIS / Bibtex

APA

Bayen, A., Yafout, M., El Bouamri, M., Ait Haj Said, A., & Benmoussa, A. (2026). BACE1 Inhibitors: Design, Synthesis, Structure–Activity Relationships, and Therapeutic Applications in Alzheimer’s Disease and Beyond – An Updated Review. Journal of the Turkish Chemical Society Section A: Chemistry, 2026-1, 1-33. https://doi.org/10.18596/jotcsa.1827742

AMA

1.Bayen A, Yafout M, El Bouamri M, Ait Haj Said A, Benmoussa A. BACE1 Inhibitors: Design, Synthesis, Structure–Activity Relationships, and Therapeutic Applications in Alzheimer’s Disease and Beyond – An Updated Review. JOTCSA. 2026;(2026-1):1-33. doi:10.18596/jotcsa.1827742

Chicago

Bayen, Amine, Mohamed Yafout, Mohamed El Bouamri, Amal Ait Haj Said, and Adnane Benmoussa. 2026. “BACE1 Inhibitors: Design, Synthesis, Structure–Activity Relationships, and Therapeutic Applications in Alzheimer’s Disease and Beyond – An Updated Review”. Journal of the Turkish Chemical Society Section A: Chemistry, no. 2026-1: 1-33. https://doi.org/10.18596/jotcsa.1827742.

EndNote

Bayen A, Yafout M, El Bouamri M, Ait Haj Said A, Benmoussa A (May 1, 2026) BACE1 Inhibitors: Design, Synthesis, Structure–Activity Relationships, and Therapeutic Applications in Alzheimer’s Disease and Beyond – An Updated Review. Journal of the Turkish Chemical Society Section A: Chemistry 2026-1 1–33.

IEEE

[1]A. Bayen, M. Yafout, M. El Bouamri, A. Ait Haj Said, and A. Benmoussa, “BACE1 Inhibitors: Design, Synthesis, Structure–Activity Relationships, and Therapeutic Applications in Alzheimer’s Disease and Beyond – An Updated Review”, JOTCSA, no. 2026-1, pp. 1–33, May 2026, doi: 10.18596/jotcsa.1827742.

ISNAD

Bayen, Amine - Yafout, Mohamed - El Bouamri, Mohamed - Ait Haj Said, Amal - Benmoussa, Adnane. “BACE1 Inhibitors: Design, Synthesis, Structure–Activity Relationships, and Therapeutic Applications in Alzheimer’s Disease and Beyond – An Updated Review”. Journal of the Turkish Chemical Society Section A: Chemistry. 2026-1 (May 1, 2026): 1-33. https://doi.org/10.18596/jotcsa.1827742.

JAMA

1.Bayen A, Yafout M, El Bouamri M, Ait Haj Said A, Benmoussa A. BACE1 Inhibitors: Design, Synthesis, Structure–Activity Relationships, and Therapeutic Applications in Alzheimer’s Disease and Beyond – An Updated Review. JOTCSA. 2026;:1–33.

MLA

Bayen, Amine, et al. “BACE1 Inhibitors: Design, Synthesis, Structure–Activity Relationships, and Therapeutic Applications in Alzheimer’s Disease and Beyond – An Updated Review”. Journal of the Turkish Chemical Society Section A: Chemistry, no. 2026-1, May 2026, pp. 1-33, doi:10.18596/jotcsa.1827742.

Vancouver

1.Amine Bayen, Mohamed Yafout, Mohamed El Bouamri, Amal Ait Haj Said, Adnane Benmoussa. BACE1 Inhibitors: Design, Synthesis, Structure–Activity Relationships, and Therapeutic Applications in Alzheimer’s Disease and Beyond – An Updated Review. JOTCSA. 2026 May 1;(2026-1):1-33. doi:10.18596/jotcsa.1827742