HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

REVIEW: γ-Secretase inhibitors for the treatment of Alzheimer's disease: The current state.

AbstractAIMS:
Drugs currently used for the treatment of Alzheimer's disease (AD) partially stabilize patients' symptoms without modifying disease progression. Brain accumulation of oligomeric species of β-amyloid (Aβ) peptides, the principal components of senile plaques, is believed to play a crucial role in the development of AD. Based on this hypothesis, huge efforts are being spent to identify drugs able to interfere with proteases regulating Aβ formation from amyloid precursor protein (APP). This article briefly reviews the profile of γ-secretase inhibitors, compounds that inhibit γ-secretase, the pivotal enzyme that generates Aβ, and that have reached the clinic.
DISCUSSION:
Several classes of potent γ-secretase inhibitors have been designed and synthesized. Preclinical studies have indicated that these compounds are able to lower brain Aβ concentrations and, in some cases, reduce Aβ plaque deposition in transgenic mouse models of AD. The most developmentally advanced of these compounds is semagacestat, presently in Phase III clinical trials. In animals, semagacestat reduced Aβ levels in the plasma, cerebrospinal fluid (CSF), and the brain. However, studies have not reported on its cognitive effects. Studies in both healthy volunteers and patients with AD have demonstrated a dose-dependent inhibition of plasma Aβ levels, and a recent study in healthy subjects demonstrated a robust, dose-dependent inhibition of newly generated Aβ in the CSF after single oral doses.
CONCLUSIONS:
Unfortunately, γ-secretase inhibitors may cause intestinal goblet cell hyperplasia, thymus atrophy, decrease in lymphocytes, and alterations in hair color, effects associated with the inhibition of the cleavage of Notch, a protein involved in cell development and differentiation. Nevertheless, at least other two promising γ-secretase inhibitors are being tested clinically. This class of drugs represents a major hope to slow the rate of decline of AD.
AuthorsFrancesco Panza, Vincenza Frisardi, Bruno P Imbimbo, Cristiano Capurso, Giancarlo Logroscino, Daniele Sancarlo, Davide Seripa, Gianluigi Vendemiale, Alberto Pilotto, Vincenzo Solfrizzi
JournalCNS neuroscience & therapeutics (CNS Neurosci Ther) Vol. 16 Issue 5 Pg. 272-84 (Oct 2010) ISSN: 1755-5949 [Electronic] England
PMID20560993 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
Copyright© 2010 Blackwell Publishing Ltd.
Chemical References
  • Amyloid beta-Peptides
  • Enzyme Inhibitors
  • Amyloid Precursor Protein Secretases
Topics
  • Alzheimer Disease (drug therapy)
  • Amyloid Precursor Protein Secretases (antagonists & inhibitors, metabolism)
  • Amyloid beta-Peptides (metabolism)
  • Enzyme Inhibitors (therapeutic use)
  • Humans

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: