title: Advances in the identification of γ-secretase inhibitors for the treatment of Alzheimer's disease.
abstract: BACKGROUND
  In an attempt of altering the natural history of Alzheimer's disease (AD), several compounds have been developed with the aim of inhibiting γ-secretase, the enzymatic complex generating β-amyloid (Aβ) peptides (Aβ(1 - 40) and Aβ(1 - 42)), from amyloid precursor protein (APP). APP is believed to be involved in the pathophysiological cascade of AD.
  
  
  METHODS
  This article briefly reviews the profile of γ-secretase inhibitors that have reached the clinic. The paper reviews studies from the primary English literature on γ-secretase inhibitors published before November 2011, searching through the PubMed database of NCBI by author and the following keywords: drugs targeting β-amyloid, γ-secretase inhibitors, dementia syndromes and Alzheimer's disease.
  
  
  CONCLUSIONS
  Studies in both transgenic and non-transgenic animal models of AD have indicated that γ-secretase inhibitors, administered by the oral route, are able to lower brain Aβ concentrations. However, scanty data are available on the effects of these compounds on brain Aβ deposition after prolonged administration. γ-Secretase inhibitors may cause significant toxicity in experimental animals and in humans believed to be associated with the inhibition of the cleavage of Notch, a transmembrane receptor involved in regulating cell-fate decisions. Unfortunately, two large Phase III clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of a detrimental cognitive and functional effects of the drug, possibly due to its lack of selectivity on APP processing. New APP-selective γ-secretase inhibitors are being developed with the hope of overcoming the previous setbacks.
authors.affiliation: IRCCS Casa Sollievo della Sofferenza, Geriatric Unit and Gerontology-Geriatric Research Laboratory, San Giovanni Rotondo, Foggia, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: D'Onofrio
authors.forename: Francesco
authors.initials: F
authors.lastname: Panza
authors.forename: Vincenza
authors.initials: V
authors.lastname: Frisardi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Solfrizzi
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Imbimbo
authors.forename: Giulia
authors.initials: G
authors.lastname: Paroni
authors.forename: Leandro
authors.initials: L
authors.lastname: Cascavilla
authors.forename: Davide
authors.initials: D
authors.lastname: Seripa
authors.forename: Alberto
authors.initials: A
authors.lastname: Pilotto
mesh_terms: D000409:Alanine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001381:Azepines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D017326:Clinical Trials, Phase III as Topic; D004195:Disease Models, Animal; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001381:Azepines; D004791:Enzyme Inhibitors; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine