Alzheimer's disease (AD) is a debilitating neurodegenerative disorder which imparts tremendous suffering upon more than 20 million people worldwide [1]. Current marketed therapy treats the symptoms and not the etiology of the disease, with cholinesterase inhibitors prescribed for mild to moderate AD and the NMDA antagonist memantine for moderate to severe AD [2]. There is broad consensus that amyloid peptides are involved in the progression of the disease [3-8]. This is supported by genetic mapping of the minor familiar forms of AD to mutations that either increase the overall production of β-amyloid1-40(42) (Aβ) or produce increased amounts of β-amyloid1-42 which is more prone to aggregation. Oligomeric β-amyloid1-42 (Aβ) and related peptides are neurotoxic in cell culture. In this chapter the focus will be on BACE (BACE-1, β-secretase, memapsin-2, Asp-2: Figure 1), an aspartic protease that has captured the attention of the pharmaceutical industry because of the important role it plays in processing the Type I transmembrane amyloid precursor protein (APP) to form β-amyloid peptides [2,9-11]. BACE is responsible for the initial cleavage of APP at aspartic acid D1 of the N-terminus of the nascent Aβ peptides to give C terminal fragment C99 (β-CTF) which is subsequently cleaved by the membrane bound γ-secretase complex [12]. Alternative cleavage of APP by α-secretase provides innocuous peptide fragments. There are now more than 15 publications and 75 patent applications disclosing structures that inhibit BACE, and this review seeks to capture the field as of May, 2005. © 2005 Elsevier Inc. All rights reserved.
