1350320-98-7Relevant academic research and scientific papers
Design, synthesis, and qualitative structure-activity evaluations of novel β-secretase inhibitors as potential Alzheimer's drug leads
Al-Tel, Taleb H.,Semreen, Mohammad H.,Al-Qawasmeh, Raed A.,Schmidt, Marco F.,El-Awadi, Raafat,Ardah, Mustafa,Zaarour, Rania,Rao, Shashidhar N.,El-Agnaf, Omar
, p. 8373 - 8385 (2011)
We have identified highly selective imidazopyr-idines armed with benzimidazol and/or arylimidazole as potent β-secretase inhibitors. The most effective and selective analogues demonstrated low nanomolar potency for the BACE1 enzyme as measured by FRET and cell-based (ELISA) assays and exhibited comparable affinity (KI) and high ligand efficiency (LE). In addition, these motifs were highly selective (>200) against the structurally related aspartyl protease BACE2. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on the previously reported hydroxyethylene transition state inhibitor derived from iso-phthalic acid I. Of the most potent compounds, 34 displayed an IC50 for BACE1 of 18 nM and exhibited cellular activity with an EC50 of 37 nM in the cell-based ELISA assay, as well as high affinity (KI = 17 nM) and ligand efficiency (LE = 1.7 kJ/mol). Compound 34 was found to be 204-fold more selective for BACE1 compared to the closely related aspartyl protease BACE2. (Figure presented)
