Abstract

Alzheimer's disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-ß (Aß) in the brain, with a length of 42 and 40 amino acids. A-secretase cleaves amyloid-ß protein precursor (AßPP) producing the membrane-bound fragment CTFA and the soluble fragment sAßPPA with neuroprotective activity; ß-secretase produces membrane-bound fragment CTFß and a soluble fragment sAßPPß. After A-secretase cleavage of AßPP, ?-secretase cleaves CTFA to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFß is cleaved by ?-secretase producing AICD as well as Aß in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as A-secretase activity enhancers, ß-secretase inhibitors (BACE-1), and ?-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aß42. In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979 Verubecestat, LY2886721, Lanabecestat, LY2811376 and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aß production did not recover cognitive functions or reverse disease progress. Novel strategies are being developed, aiming at a partial reduction of Aß production, such as the development of ?-secretase modulators or A-secretase activity enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.