beta-secretase 1 | A1: Pepsin | IUPHAR/BPS Guide to PHARMACOLOGY

beta-secretase 1

Target id: 2330

Nomenclature: beta-secretase 1

Abbreviated Name: BACE1

Family: A1: Pepsin

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for beta-secretase 1 in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 501 11q23-q24 BACE1 beta-secretase 1
Mouse 1 501 9 A5.2 Bace1 beta-site APP cleaving enzyme 1
Rat 1 501 8q22 Bace1 beta-secretase 1
Previous and Unofficial Names
APP beta-secretase | ASP2 | aspartyl protease 2 | Bace | beta-site amyloid precursor protein cleaving enzyme 1 | memapsin-2 | beta-site APP-cleaving enzyme 1
Database Links
Specialist databases
MEROPS A01.004 (Hs)
Other databases
BRENDA
CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 3.4.23.46

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
compound 16 [PMID: 23412139] Hs Competitive 8.8 pKi 21
pKi 8.8 (Ki 1.7x10-9 M) [21]
verubecestat Hs Competitive 8.8 pKi 20
pKi 8.8 (Ki 1.753x10-9 M) [20]
AZ-4217 Hs Competitive 8.7 pKi 5
pKi 8.7 (Ki 1.8x10-9 M) [5]
compound 13 [PMID: 23412139] Hs Inhibition 8.1 pKi 21
pKi 8.1 (Ki 7.8x10-9 M) [21]
AZD3839 Hs Competitive 7.6 pKi 11
pKi 7.6 (Ki 2.61x10-8 M) [11]
TAK-070 Hs Non-competitive 4.7 pKi 7
pKi 4.7 (Ki 1.9x10-5 M) [7]
compound 15 [PMID: 25699151] Hs Inhibition 9.5 pIC50 3
pIC50 9.5 (IC50 3x10-10 M) [3]
AMG-8718 Hs Inhibition 9.1 pIC50 4
pIC50 9.1 (IC50 7x10-10 M) [4]
PF-06684511 Hs Inhibition 9.1 pIC50 23
pIC50 9.1 (IC50 7x10-10 M) [23]
lanabecestat Hs Competitive 8.7 pIC50 1
pIC50 8.7 (IC50 2.2x10-9 M) [1]
compound 11d [PMID: 23981898] Hs Competitive 8.4 pIC50 19
pIC50 8.4 (IC50 4x10-9 M) [19]
NB-360 Hs Inhibition 8.3 pIC50 16
pIC50 8.3 (IC50 5x10-9 M) [16]
compound 2 [PMID: 22911925] Hs Competitive 8.3 pIC50 22
pIC50 8.3 (IC50 5.5x10-9 M) [22]
elenbecestat Hs Inhibition 8.1 pIC50 12
pIC50 8.1 (IC50 7x10-9 M) [12]
PF-06751979 Hs Inhibition 8.1 pIC50 17
pIC50 8.1 (IC50 7.3x10-9 M) [17]
atabecestat Hs Inhibition 8.0 pIC50 13
pIC50 8.0 (IC50 9.8x10-9 M) [13]
oxazine 89 Hs Competitive 7.9 pIC50 8
pIC50 7.9 (IC50 1.2x10-8 M) [8]
compound J [PMID: 21907142] Hs Inhibition 7.7 pIC50 6
pIC50 7.7 (IC50 1.8x10-8 M) [6]
LY2886721 Hs Competitive 7.7 pIC50 14
pIC50 7.7 (IC50 2.03x10-8 M) [14]
example 2 [WO2013004676] Hs Inhibition 7.6 pIC50 2
pIC50 7.6 (IC50 2.6x10-8 M) [2]
AZ3971 Hs Competitive 7.5 pIC50 9
pIC50 7.5 (IC50 3x10-8 M) [9]
RO5508887 Hs Inhibition 7.5 pIC50 10
pIC50 7.5 (IC50 3x10-8 M) [10]
LY2811376 Hs Competitive 6.6 pIC50 15
pIC50 6.6 (IC50 2.39x10-7 M) [15]
Compound 12 [PMID:28626832] Hs Inhibition 3.3 pIC50 18
pIC50 3.3 (IC50 5x10-4 M) [18]

References

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1. Blass B. (2012) Compounds and Their Use as BACE Inhibitors: Patent Highlight. ACS Med Chem Lett, 3 (11): 875-6. [PMID:24900397]

2. Blass B. (2013) Cyclopropyl-Fused 1,3-Thiazepines as BACE1 and BACE2 Inhibitors. ACS Med Chem Lett, 4 (4): 379-80. [PMID:24900681]

3. Cheng Y, Brown J, Judd TC, Lopez P, Qian W, Powers TS, Chen JJ, Bartberger MD, Chen K, Dunn 2nd RT et al.. (2015) An Orally Available BACE1 Inhibitor That Affords Robust CNS Aβ Reduction without Cardiovascular Liabilities. ACS Med Chem Lett, 6 (2): 210-5. [PMID:25699151]

4. Dineen TA, Chen K, Cheng AC, Derakhchan K, Epstein O, Esmay J, Hickman D, Kreiman CE, Marx IE, Wahl RC et al.. (2014) Inhibitors of β-site amyloid precursor protein cleaving enzyme (BACE1): identification of (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine (AMG-8718). J. Med. Chem., 57 (23): 9811-31. [PMID:25363711]

5. Eketjäll S, Janson J, Jeppsson F, Svanhagen A, Kolmodin K, Gustavsson S, Radesäter AC, Eliason K, Briem S, Appelkvist P et al.. (2013) AZ-4217: a high potency BACE inhibitor displaying acute central efficacy in different in vivo models and reduced amyloid deposition in Tg2576 mice. J. Neurosci., 33 (24): 10075-84. [PMID:23761903]

6. Esterházy D, Stützer I, Wang H, Rechsteiner MP, Beauchamp J, Döbeli H, Hilpert H, Matile H, Prummer M, Schmidt A et al.. (2011) Bace2 is a β cell-enriched protease that regulates pancreatic β cell function and mass. Cell Metab., 14 (3): 365-77. [PMID:21907142]

7. Fukumoto H, Takahashi H, Tarui N, Matsui J, Tomita T, Hirode M, Sagayama M, Maeda R, Kawamoto M, Hirai K et al.. (2010) A noncompetitive BACE1 inhibitor TAK-070 ameliorates Abeta pathology and behavioral deficits in a mouse model of Alzheimer's disease. J. Neurosci., 30 (33): 11157-66. [PMID:20720123]

8. Hilpert H, Guba W, Woltering TJ, Wostl W, Pinard E, Mauser H, Mayweg AV, Rogers-Evans M, Humm R, Krummenacher D et al.. (2013) β-Secretase (BACE1) inhibitors with high in vivo efficacy suitable for clinical evaluation in Alzheimer's disease. J. Med. Chem., 56 (10): 3980-95. [PMID:23590342]

9. Holenz J et al. (2011) 5h-pyrrolo[3,4- gbp >]pyrazin-7-amine derivatives inhibitors of beta-secretase. Patent number: WO2011002409. Assignee: AstraZeneca. Priority date: 03/07/2009. Publication date: 06/01/2011.

10. Jacobsen H, Ozmen L, Caruso A, Narquizian R, Hilpert H, Jacobsen B, Terwel D, Tanghe A, Bohrmann B. (2014) Combined treatment with a BACE inhibitor and anti-Aβ antibody gantenerumab enhances amyloid reduction in APPLondon mice. J. Neurosci., 34 (35): 11621-30. [PMID:25164658]

11. Jeppsson F, Eketjäll S, Janson J, Karlström S, Gustavsson S, Olsson LL, Radesäter AC, Ploeger B, Cebers G, Kolmodin K et al.. (2012) Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease. J. Biol. Chem., 287 (49): 41245-57. [PMID:23048024]

12. Juichi, S et al.. (2009) Fused aminodihydrothiazine derivatives. Patent number: US20090209755. Assignee: Eisai. Priority date: 18/01/2008. Publication date: 20/08/2009.

13. Koriyama, Y. Discovery and synthesis of JNJ-​54861911, a novel orally active BACE1 inhibitor. Accessed on 28/05/2018. Modified on 28/05/2018. CiteUlike, http://www.citeulike.org/user/cdsouthan/article/14595136

14. May P, Boggs L, Brier R, Calligaro D, Citron M, Day T, Lin S, Lindstrom T, Mergott D, Monk S et al.. (2012) Preclinical characterizathion of LY2886721: A BACE1 inhibitor in clinical development for early Alzheimer's disease. Alzheimer's and Dementia, 8 (4): 95.

15. May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM, Boggs LN, Monk SA, Mathes BM, Mergott DJ, Watson BM et al.. (2011) Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor. J. Neurosci., 31 (46): 16507-16. [PMID:22090477]

16. Neumann U, Rueeger H, Machauer R, Veenstra SJ, Lueoend RM, Tintelnot-Blomley M, Laue G, Beltz K, Vogg B, Schmid P et al.. (2015) A novel BACE inhibitor NB-360 shows a superior pharmacological profile and robust reduction of amyloid-β and neuroinflammation in APP transgenic mice. Mol Neurodegener, 10: 44. [PMID:26336937]

17. O'Neill BT, Beck EM, Butler CR, Nolan CE, Gonzales C, Zhang L, Doran SD, Lapham K, Buzon LM, Dutra JK et al.. (2018) Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant, β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation. J. Med. Chem., 61 (10): 4476-4504. [PMID:29613789]

18. Rombouts FJR, Alexander R, Cleiren E, De Groot A, Carpentier M, Dijkmans J, Fierens K, Masure S, Moechars D, Palomino-Schätzlein M et al.. (2017) Fragment Binding to β-Secretase 1 without Catalytic Aspartate Interactions Identified via Orthogonal Screening Approaches. ACS Omega, 2 (2): 685-697. [PMID:28626832]

19. Rueeger H, Lueoend R, Machauer R, Veenstra SJ, Jacobson LH, Staufenbiel M, Desrayaud S, Rondeau JM, Möbitz H, Neumann U. (2013) Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective β-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid β-peptides. Bioorg. Med. Chem. Lett., 23 (19): 5300-6. [PMID:23981898]

20. Scott JD et al.. (2015) Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use. Patent number: US8940748. Assignee: Merck Sharp & Dohme. Priority date: 08/10/2009. Publication date: 27/01/2015.

21. Stamford AW, Scott JD, Li SW, Babu S, Tadesse D, Hunter R, Wu Y, Misiaszek J, Cumming JN, Gilbert EJ et al.. (2012) Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS Aβ Reduction. ACS Med Chem Lett, 3 (11): 897-902. [PMID:23412139]

22. Wood S, Wen PH, Zhang J, Zhu L, Luo Y, Babu-Khan S, Chen K, Pham R, Esmay J, Dineen TA et al.. (2012) Establishing the relationship between in vitro potency, pharmacokinetic, and pharmacodynamic parameters in a series of orally available, hydroxyethylamine-derived β-secretase inhibitors. J. Pharmacol. Exp. Ther., 343 (2): 460-7. [PMID:22911925]

23. Zhang L, Chen L, Dutra JK, Beck EM, Nag S, Takano A, Amini N, Arakawa R, Brodney MA, Buzon LM et al.. (2018) Identification of a Novel Positron Emission Tomography (PET) Ligand for Imaging β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE-1) in Brain. J. Med. Chem., 61 (8): 3296-3308. [PMID:29356535]

How to cite this page

A1: Pepsin: beta-secretase 1. Last modified on 12/06/2018. Accessed on 14/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2330.