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Abstract: A similarity search on the structural analogs of an inhibitor of BACE-1 with IC50 2.8μM, which contained a P1 benzothiazole group together with a triazine ring linked by a secondary amine group, was described in this Letter and some more potent inhibitors against BACE-1 were identified. The most potent compound 5 (IC50 =0.12μM) increases the inhibitory potency by 24 folds. Our results suggest that a pyrrolidinyl side group at the P3′ and P4′ of the inhibitors are favored for strong inhibition and a small aromatic group at the P4 position is also essential to the potency. [ABSTRACT FROM AUTHOR]

Abstract: Nowadays identification of novel non-peptide β-secretase (BACE-1, hereinafter) inhibitors with low cytotoxicity and good blood–brain barrier (BBB) property holds common interest of drug discovery for Alzheimer’s disease. Twenty SPECS compounds were tested in BACE-1 FRET assays and methylthiazoletetrazolium (MTT) cytotoxicity experiment. Two compounds: 2 and 15 demonstrated IC50 values of 0.53 and 9.4μM. In addition, 2 showed least toxic effect to the neuroblastoma cells. The results from both in silico and in vitro studies provided new pharmacophoric entities for chemical synthesis and optimization on the current discovered BACE-1 small molecule inhibitors. [Copyright &y& Elsevier]

Abstract: This Letter describes an efficient approach by integrating virtual screening with bioassay technology for finding small organic inhibitors targeting β-secretase (BACE-1). Fifteen hits with inhibitory potencies ranging from 2.8 to 118μM (IC50) against β-secretase were successfully identified. Compound 12 with IC50 of 2.8μM is the most potent hit against BACE-1. Docking simulation from gold 3.0 suggests putative binding mode of 12 in BACE-1 and potential key pharmacophore groups for further designing of non-peptide compounds as more powerful inhibitors against BACE-1. [Copyright &y& Elsevier]