gamma-Secretase as a target for drug intervention in Alzheimer's disease.
gamma-Secretase is a critical enzyme involved in the production of amyloid-beta (Abeta) peptide, one of the main pathological hallmarks of Alzheimer's disease. gamma-Secretase cleaves the beta-amyloid precursor protein (betaAPP) at a position predicted to be within the membrane. In addition to betaAPP, gamma-secretase cleaves a range of other substrates. Thus, a key question in the development of gamma-secretase inhibitors for preventing Abeta production is whether undesired mechanism-based side effects may result from inhibition of cleavage of other substrates, and if so whether a suitable window exists to reduce brain Abeta. In this review, progress in the development of small-molecule inhibitors will be described, and potential toxicity issues associated with the development of gamma-secretase inhibitors discussed.
Harrison
Timothy
T
Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow Essex CM20 2QR, UK. timothy_harrison@merck.com
Churcher
Ian
I
Beher
Dirk
D
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D017322:Clinical Trials, Phase II as Topic; D015195:Drug Design; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D013678:Technology, Pharmaceutical / Q000379:methods
D016564:Amyloid beta-Protein Precursor; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human