BACE-1 is one of the major Alzheimer's disease target [38, 39, 40] . To find novel BACE-1 inhibitors, a lot of academic research centres and pharmaceutical industries are quite active in this field. Merck research group performed in vitro highthroughput screening (HTS) and found a single molecule (a 1,3,5 trisubstituted benzene) as a hit from a multi-million compound library [73] . Johnson and Johnson also reported a novel cyclic guanidine screening lead, the initial screening lead had an IC 50 value of 900 nM [45] . Astex Therapeutics has taken a fragment-based lead generation approach [74] . After the virtual screening of a fragment library, a small number of potential structures were soaked with BACE-1 crystals in anticipation of obtaining a co-crystal with the enzyme. Huang et al. performed in silico Screening of 180,000 small chemicals, they found 10 diacylurea inhibitors showed an IC 50 value lower than 100 mM in a enzymatic assay and four of them were cell penetrant (EC 50 ,20 mM) [75] .