Design, synthesis and SAR analysis of potent BACE1 inhibitors: Possible lead drug candidates for Alzheimer's disease

We have identified potent isophthalic acid derivatives armed with imidazol and indolyl groups as potent beta-secretase inhibitors. The most effective analogs demonstrated low nano-molar potency for the BACE1 (beta-secretase cleaving enzyme) as measured by FRET (Fluorescence Resonance Energy Transfer) and cell-based (ELISA) assays. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on previously reported hydroxyethylene transition state inhibitor derived from isophthalic acid I. In the FRET assay, the most potent compound, 10a, displayed an IC50 value for BACE1 of 75 nM, and exhibited cellular activity with an EC50 value of 0.81 mu M. On the other hand, compound 11b was found to be the most potent compound in the cell-based assay with an EC50 value of 0.29 mu M. (C) 2016 Elsevier Masson SAS. All rights reserved.