Recent advances in the development of gamma-secretase inhibitors.
Alzheimer's disease is a neurodegenerative disorder that exerts a huge psychological and social toll in modern societies. The current hypothesis for the cause of this illness is that it is the result of aberrant production of beta-amyloid (A beta) and plaque deposition in the brain of affected individuals. New therapeutic interventions seek to stop or even reverse the course of the disease by inhibiting this aggregation or reducing A beta formation. The use of inhibitors of gamma-secretase, a key enzyme in the production of A beta, is currently undergoing preclinical and clinical evaluation. Small molecule inhibitors which demonstrate efficacy in reducing A beta burden in mice have thus been recently discovered. This review summarizes the development of such inhibitors in light of our current understanding of the function of gamma-secretase. It also provides an evaluation of the therapeutic potential for this class of compounds with the recent discovery of other biochemical pathways associated with gamma-secretase, such as Notch signaling.
Josien
Hubert
H
Schering-Plough Research Institute, CV and CNS Medicinal Chemistry Department, 2015 Galloping Hill Road, Kenilworth, NJ 07033-1300, USA. hubert.josien@spcorp.com
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D013678:Technology, Pharmaceutical / Q000379:methods / Q000639:trends*
D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human