Target Information

Target General Infomation
Target ID
T73992
Former ID
TTDC00092
Target Name
Beta-secretase
Synonyms
BACE1; ASP2; Aspartyl protease 2; BACE; Beta-site AbetaPP-cleaving enzyme; Beta-site amyloid precursor protein cleaving enzyme; Memapsin-2; Membrane-associated aspartic protease 2; Transmembrane aspartic protease
Target Type
Clinical Trial
Disease Alzheimer disease [ICD9: 331; ICD10: G30]
Cardiovascular disorder [ICD10: I00-I99]
Diabetes [ICD9: 253.5, 588.1; ICD10: E23.2, N25.1]
Diabetic nephropathy [ICD9: 250.4; ICD10: E11.21]
Rheumatoid arthritis [ICD9: 710-719, 714; ICD10: M05-M06]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Function
Responsible for the proteolytic processing of the amyloid precursor protein (app). Cleaves at the amino terminus of the a-beta peptide sequence, between residues 671 and 672 of app, leads to the generation and extracellular release of beta-cleaved soluble liquid.
BioChemical Class
Peptidase
Target Validation
T73992
EC Number
EC 3.4.23.46
Drugs and Mode of Action
Drug(s) AZD3293 Drug Info Phase 2/3 Alzheimer disease [524922], [542739]
E-2609 Drug Info Phase 2 Alzheimer disease [525035]
LY2886721 Drug Info Phase 2 Alzheimer disease [541610], [551857]
R-flurbiprofen Drug Info Phase 2 Discovery agent [521532], [542364]
AZD-3839 Drug Info Phase 1 Alzheimer disease [523465], [541975]
CTS-21166 Drug Info Phase 1 Alzheimer disease [522234]
HPP-854 Drug Info Phase 1 Alzheimer disease [523704]
LY-2811376 Drug Info Phase 1 Alzheimer disease [522571], [541979]
RG7129 Drug Info Phase 1 Alzheimer disease [523894]
AZ-4217 Drug Info Clinical trial Rheumatoid arthritis [532395]
compound 11d Drug Info Clinical trial Cardiovascular disorder [532465]
compound 2 Drug Info Clinical trial Diabetes [531865], [532013]
oxazine 89 Drug Info Clinical trial Diabetic nephropathy [532315]
TAK-070 Drug Info Clinical trial Solid tumours [531110]
SCH-1359113 Drug Info Preclinical Alzheimer disease [548013]
DNP-004089 Drug Info Terminated Alzheimer disease [547890]
Inhibitor (-)-CATECHINGALLATE Drug Info [526870]
(2S)-2'-methoxy kurarinone Drug Info [529543]
(S)-FLURBIPROFEN Drug Info [528008]
4-(2-aminoethyl)-2-cyclohexylphenol Drug Info [551374]
4-(2-aminoethyl)-2-ethylphenol Drug Info [551374]
4-(4-FLUOROBENZYL)PIPERIDINE Drug Info [551374]
5,5-Diphenyl-2-iminohydantoin Drug Info [530611]
6-[2-(1H-INDOL-6-YL)ETHYL]PYRIDIN-2-AMINE Drug Info [551374]
7-Phloroethol Drug Info [530909]
AP-2243 Drug Info [529149]
AZ-4217 Drug Info [532395]
AZ3971 Drug Info [543593]
AZD-3839 Drug Info [532073]
Bis-7-tacrine Drug Info [530301]
Carbocyclic Peptidomimetic Drug Info [527675]
compound 11d Drug Info [532465]
compound 16 Drug Info [532235]
compound 2 Drug Info [532013]
compound J Drug Info [531619]
CTS-21166 Drug Info [525343]
DIECKOL Drug Info [530909]
DIOXINODEHYDROECKOL Drug Info [530909]
DNP-004089 Drug Info [550827]
E-2609 Drug Info [544424]
Eckol Drug Info [530909]
example 2 (WO2013004676) Drug Info [532823]
Glu-Leu-Asp-Leu-(CHOH-CH2)-Ala-Ala-Glu-Phe Drug Info [527272]
GRL-7234 Drug Info [528786]
GSK-188909 Drug Info [530119]
KMI-172 Drug Info [528637]
KMI-494 Drug Info [528637]
KMI-538 Drug Info [528637]
KMI-596 Drug Info [530840]
KURARINONE Drug Info [529543]
KUSHENOL A Drug Info [529543]
LEACHIANONE A Drug Info [529543]
LY-2811376 Drug Info [531702], [551187]
MMI-175 Drug Info [551393]
N-(1-benzylpiperidin-4-yl)-4-sulfanylbutanamide Drug Info [551374]
N~3~-(3-PYRIDIN-3-YLBENZYL)PYRIDINE-2,3-DIAMINE Drug Info [551374]
N~3~-BENZYLPYRIDINE-2,3-DIAMINE Drug Info [551374]
OM00-3 Drug Info [528788]
Oxalyl-DAP derivative Drug Info [527323]
oxazine 89 Drug Info [532315]
PHLOROFUCOFUROECKOL A Drug Info [530909]
R-flurbiprofen Drug Info [528008]
SCH-1359113 Drug Info [551869]
TAK-070 Drug Info [531110]
TRIPHLOROETHOL A Drug Info [530909]
Modulator AZD3293 Drug Info [551416]
HPP-854 Drug Info [533118]
LY2886721 Drug Info
RG7129 Drug Info [533118]
verubecestat Drug Info [533118]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
References
Ref 521532ClinicalTrials.gov (NCT00045123) R-Flurbiprofen in Treating Patients With Localized Prostate Cancer at Risk of Recurrence. U.S. National Institutes of Health.
Ref 522234ClinicalTrials.gov (NCT00621010) Safety Study of CTS21166 to Treat Alzheimer Disease. U.S. National Institutes of Health.
Ref 522571ClinicalTrials.gov (NCT00838084) A Safety Study of LY2811376 Single Doses in Healthy Subjects. U.S. National Institutes of Health.
Ref 523465ClinicalTrials.gov (NCT01348737) Assessment of Safety, Tolerability and Blood Concentrations of Single Doses of AZD3839 in Healthy Volunteers. U.S. National Institutes of Health.
Ref 523704ClinicalTrials.gov (NCT01482013) Safety Study of HPP854 in Subjects With Mild Cognitive Impairment or a Diagnosis of Mild Alzheimer's Disease. U.S. National Institutes of Health.
Ref 523894ClinicalTrials.gov (NCT01592331) A Pharmacodynamic and Pharmacokinetic Study of RO5508887 in Healthy Volunteers. U.S. National Institutes of Health.
Ref 524922ClinicalTrials.gov (NCT02245737) An Efficacy and Safety Study of AZD3293 in Early Alzheimer's Disease. U.S. National Institutes of Health.
Ref 525035ClinicalTrials.gov (NCT02322021) Dose-Finding Study To Evaluate Safety, Tolerability, and Efficacy of E2609 in Subjects With Mild Cognitive Impairment Due to Alzheimer's Disease (Prodromal Alzheimer's Disease) and Mild Dementia Due to Alzheimer's Disease. U.S. National Institutes of Health.
Ref 531110A noncompetitive BACE1 inhibitor TAK-070 ameliorates Abeta pathology and behavioral deficits in a mouse model of Alzheimer's disease. J Neurosci. 2010 Aug 18;30(33):11157-66.
Ref 531865Design and synthesis of potent, orally efficacious hydroxyethylamine derived beta-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors. J Med Chem. 2012 Nov 8;55(21):9025-44.
Ref 532013Establishing the relationship between in vitro potency, pharmacokinetic, and pharmacodynamic parameters in a series of orally available, hydroxyethylamine-derived beta-secretase inhibitors. J Pharmacol Exp Ther. 2012 Nov;343(2):460-7.
Ref 532315beta-Secretase (BACE1) inhibitors with high in vivo efficacy suitable for clinical evaluation in Alzheimer's disease. J Med Chem. 2013 May 23;56(10):3980-95.
Ref 532395AZ-4217: a high potency BACE inhibitor displaying acute central efficacy in different in vivo models and reduced amyloid deposition in Tg2576 mice. J Neurosci. 2013 Jun 12;33(24):10075-84.
Ref 532465Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective beta-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid beta-peptides. Bioorg Med Chem Lett. 2013 Oct 1;23(19):5300-6.
Ref 541610(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6475).
Ref 541975(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6931).
Ref 541979(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6936).
Ref 542364(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7340).
Ref 542739(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7789).
Ref 547890Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020178)
Ref 548013Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021196)
Ref 551857Clinical pipeline report, company report or official report of Eli Lilly.
Ref 525343ClinicalTrials.gov (NCT00621010) Safety Study of CTS21166 to Treat Alzheimer Disease. U. S. National Institutes of Health. 2008.
Ref 526870Bioorg Med Chem Lett. 2003 Nov 17;13(22):3905-8.Green tea catechins as a BACE1 (beta-secretase) inhibitor.
Ref 527272J Med Chem. 2004 Nov 4;47(23):5791-7.Efficient evaluation of binding free energy using continuum electrostatics solvation.
Ref 527323Bioorg Med Chem Lett. 2005 Jan 3;15(1):211-5.Design and synthesis of highly active Alzheimer's beta-secretase (BACE1) inhibitors, KMI-420 and KMI-429, with enhanced chemical stability.
Ref 527675J Med Chem. 2005 Aug 11;48(16):5175-90.Structure-based design, synthesis, and memapsin 2 (BACE) inhibitory activity of carbocyclic and heterocyclic peptidomimetics.
Ref 528008Bioorg Med Chem Lett. 2006 Apr 15;16(8):2219-23. Epub 2006 Feb 7.The geminal dimethyl analogue of Flurbiprofen as a novel Abeta42 inhibitor and potential Alzheimer's disease modifying agent.
Ref 528637Bioorg Med Chem Lett. 2007 Mar 15;17(6):1629-33. Epub 2007 Jan 8.Design and synthesis of BACE1 inhibitors containing a novel norstatine derivative (2R,3R)-3-amino-2-hydroxy-4-(phenylthio)butyric acid.
Ref 528786J Med Chem. 2007 May 17;50(10):2399-407. Epub 2007 Apr 14.Design, synthesis, and X-ray structure of potent memapsin 2 (beta-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands.
Ref 528788Bioorg Med Chem. 2007 Jun 15;15(12):4136-43. Epub 2007 Mar 30.Synthesis and biological evaluation of phosphino dipeptide isostere inhibitor of human beta-secretase (BACE1).
Ref 529149Bioorg Med Chem Lett. 2008 Jan 1;18(1):423-6. Epub 2007 Oct 4.Multi-target-directed coumarin derivatives: hAChE and BACE1 inhibitors as potential anti-Alzheimer compounds.
Ref 529543Bioorg Med Chem. 2008 Jul 15;16(14):6669-74. Epub 2008 Jun 5.BACE1 inhibitory effects of lavandulyl flavanones from Sophora flavescens.
Ref 530119Bioorg Med Chem Lett. 2009 Jul 1;19(13):3664-8. Epub 2009 Apr 17.Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics.
Ref 530301J Med Chem. 2009 Sep 10;52(17):5365-79.Pyrano[3,2-c]quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase- and beta-amyloid-directed anti-Alzheimer compounds.
Ref 530611J Med Chem. 2010 Feb 11;53(3):951-65.Discovery of cyclic acylguanidines as highly potent and selective beta-site amyloid cleaving enzyme (BACE) inhibitors: Part I--inhibitor design and validation.
Ref 530840Bioorg Med Chem. 2010 May 1;18(9):3175-86. Epub 2010 Mar 21.Design of pentapeptidic BACE1 inhibitors with carboxylic acid bioisosteres at P1' and P4 positions.
Ref 530909Bioorg Med Chem Lett. 2010 Jun 1;20(11):3211-5. Epub 2010 Apr 24.Molecular docking studies of phlorotannins from Eisenia bicyclis with BACE1 inhibitory activity.
Ref 531110A noncompetitive BACE1 inhibitor TAK-070 ameliorates Abeta pathology and behavioral deficits in a mouse model of Alzheimer's disease. J Neurosci. 2010 Aug 18;30(33):11157-66.
Ref 531619Bace2 is a beta cell-enriched protease that regulates pancreatic beta cell function and mass. Cell Metab. 2011 Sep 7;14(3):365-77.
Ref 531702Robust central reduction of amyloid-beta in humans with an orally available, non-peptidic beta-secretase inhibitor. J Neurosci. 2011 Nov 16;31(46):16507-16.
Ref 532013Establishing the relationship between in vitro potency, pharmacokinetic, and pharmacodynamic parameters in a series of orally available, hydroxyethylamine-derived beta-secretase inhibitors. J Pharmacol Exp Ther. 2012 Nov;343(2):460-7.
Ref 532073Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease. J Biol Chem. 2012 Nov 30;287(49):41245-57.
Ref 532235Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS Abeta Reduction. ACS Med Chem Lett. 2012 Nov 8;3(11):897-902. Epub 2012 Jul 12.
Ref 532315beta-Secretase (BACE1) inhibitors with high in vivo efficacy suitable for clinical evaluation in Alzheimer's disease. J Med Chem. 2013 May 23;56(10):3980-95.
Ref 532395AZ-4217: a high potency BACE inhibitor displaying acute central efficacy in different in vivo models and reduced amyloid deposition in Tg2576 mice. J Neurosci. 2013 Jun 12;33(24):10075-84.
Ref 532465Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective beta-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid beta-peptides. Bioorg Med Chem Lett. 2013 Oct 1;23(19):5300-6.
Ref 532823Cyclopropyl-Fused 1,3-Thiazepines as BACE1 and BACE2 Inhibitors. ACS Med Chem Lett. 2013 Mar 15;4(4):379-80.
Ref 533118BACE1 inhibitor drugs in clinical trials for Alzheimer's disease. Alzheimers Res Ther. 2014 Dec 24;6(9):89.
Ref 543593(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2330).
Ref 544424Targeting the beta secretase BACE1 for Alzheimer's disease therapy. Lancet Neurol. 2014 March; 13(3): 319-329.
Ref 550827US patent application no. 8,269,019, Inhibitors.
Ref 551187Neurodegenerative disease: Inhibiting beta-secretase in humans. Nature Reviews Drug Discovery 11, 21 (January 2012).
Ref 551374The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
Ref 551393How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
Ref 551416AZD3293 A novel BACE1 inhibitor: safety, tolerability, and effects on plasma and CSF A-beta peptides following single- and multiple-dose administration. Neurobiology of Aging. May 20, 2008.
Ref 551869ACS Meeting News: Using chemistry tools to refine an Alzheimer's drug candidate. C&EN. April 5, 2010. Volume 88, Number 14 p.14.

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