title: Inhibition of BACE1 for therapeutic use in Alzheimer's disease.
abstract: Since BACE1 was reported as the beta-secretase in Alzheimer's disease (AD) over ten years ago, encouraging progress has been made toward understanding the cellular functions of BACE1. Genetic studies have further confirmed that BACE1 is essential for processing amyloid precursor protein (APP) at the beta-secretase site. Only after this cleavage can the membrane-bound APP C-terminal fragment be subsequently cleaved by gamma-secretase to release so-called AD-causing Abeta peptides. Hence, in the past decade, a wide variety of BACE1 inhibitors have been developed for AD therapy. This review will summarize the major historical events during the evolution of BACE1 inhibitors designed through different strategies of drug discovery. Although BACE1 inhibitors are expected to be safe in general, careful titration of drug dosage to avoid undesirable side effects in BACE1-directed AD therapy is also emphasized.
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Luo
authors.forename: Riqiang
authors.initials: R
authors.lastname: Yan
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057055:Aspartic Acid Proteases / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans
chemical_list: D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D057055:Aspartic Acid Proteases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human