Beta-secretase inhibition for the treatment of Alzheimer's disease--promise and challenge.
As the number of cases of Alzheimer's disease (AD) rises in all developed countries, the unmet medical need for disease-modifying pharmacotherapy continues to grow. Much of AD research has been focused on the amyloid cascade hypothesis, which states that amyloid-beta-42 (A beta 42), a proteolytic derivative of the large transmembrane protein amyloid precursor protein (APP), plays an early and crucial role in all cases of AD. Consequently, blocking the production of A beta 42 by specific inhibition of the key proteases required for A beta 42 generation is a major focus of research into AD therapy. The identification of beta-secretase, the aspartic protease that generates the N-terminus of A beta 42, has triggered a race to develop drug-like inhibitors of this enzyme, which has become one of the major AD targets. Although the biology of beta-secretase holds great promise, it will be challenging to generate drug-like inhibitors of this unusual enzyme.
Citron
Martin
M
Amgen, Department of Neuroscience, M/S 29-2-B, One Amgen Center Drive, Thousand Oaks, CA 91320, USA. mcitron@amgen.com
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors* / Q000502:physiology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000502:physiology; D010450:Endopeptidases; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans
D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human