Targeting beta or gamma-Secretase, 2010 and 2011 patents summary 

Alzheimer’s disease is pathologically characterized by the deposition of amyloid in extracellular plaques and intracellular neurofibrillary tangles in the brain. These plaques mainly comprise aggregates of β-amyloid peptides (Aβ peptides) formed from Amyloid Precursor Protein (APP) by a series of proteolytic cleavage steps involving the enzymes β- and γ-secretase.

β-Secretase (also called BACE-1 for β-site APP-cleaving enzyme) was identified as a type 1 transmembrane protein containing aspartyl protease activity and primilarly cleaves APP to yield a secreted fragment of APP (sAPPβ) and a C-terminal fragment of APP (CTFβ).

CTFβis then cleaved by γ-secretase within the membrane to yield a smaller C-terminal fragment (CTFγ) and Aβfragments of different chain length (Ab38, Ab40, Ab42). γ-Secretase is a transmembrane protein complex that includes Nicastrin, APH-1, PEN-2, and either Presenilin-1 (PS-1) or Presenilin-2 (PS-2).

An alternate cleavage by α-secretase cuts within the Aβ domain, on the contrary prevents Aβgeneration.


The potential opportunities for therapeutic interventions are then:

• Inhibitors of APP production

• Activators of α-Secretase

• Inhibitors of β- and γ-Secretase

• Aβ production Modulators

Table 1. Current Secretase inhibitors in 2010’s patents*

Company Target(s) Patent number
Amgen inc. β-Secretase WO2010030954
Astrazeneca AB γ-Secretase  WO2010132015 
Biogen idec ma inc. γ-Secretase
Bristol-Myers Squibb γ-Secretase   WO2010108067 
Astellas pharma inc. β-Secretase  WO2010042892 
Astellas pharma inc. β-Secretase  WO2010110817 
High point pharmaceuticals β-Secretase  WO2010126743 
High point pharmaceuticals β-Secretase  WO2010126745 
Hoffmann-La Roche γ-Secretase  WO2010052199 
Janssen Pharmaceutica nv. γ-Secretase  WO2010011626 
Merck Sharp and Dohme corp. γ-Secretase  WO2010019392 
Merck Sharp and Dohme corp. γ-Secretase  WO2010019393 
Merck Sharp and Dohme corp. γ-Secretase  WO2010068564 
Merck Sharp and Dohme corp. γ-Secretase  WO2010090954 
Merck Sharp and Dohme corp. β-Secretase   WO2010094242 
Modgene LLC γ-Secretase  WO2010057020 
Ortho-McNeil-Janssen Pharmaceuticals inc. γ-Secretase  WO2010070008 
Ortho-McNeil-Janssen Pharmaceuticals inc. γ-Secretase  WO2010089292 
Ortho-McNeil-Janssen Pharmaceuticals inc. γ-Secretase  WO2010094647 
Ortho-McNeil-Janssen Pharmaceuticals inc. γ-Secretase  WO2010145883
Pfizer inc. β-Secretase    WO2010058333 
Pfizer inc. γ-Secretase  WO2010100606 
Schering corporation γ-Secretase  WO2010054064 
Schering corporation γ-Secretase  WO2010054067 
Schering corporation γ-Secretase  WO2010054078 
Schering corporation γ-Secretase  WO2010056849 
Schering corporation γ-Secretase  WO2010056722 
Schering corporation γ-Secretase  WO2010075203 
Schering corporation γ-Secretase  WO2010075204 
Schering corporation γ-Secretase  WO2010147969 
Schering corporation γ-Secretase  WO2010147973 
Schering corporation γ-Secretase  WO2010147975 
Sloan-Kettering institute for cancer research γ-Secretase  WO2010075280 
Vitae pharmaceuticals inc. β-Secretase    WO2010021680 
AMICUS THERAPEUTICS, INC.  β-Secretase WO2011011181
ASTRAZENECA AB β-Secretase WO2011002409
COMENTIS, INC. β-Secretase WO2011044057
MERCK SHARP & DOHME CORP. γ-Secretase WO2011046774
PFIZER INC. γ-Secretase WO2011048525

*Source WIPO.