Design, Synthesis, and Qualitative Structure-Activity Evaluations of Novel beta-Secretase Inhibitors as Potential Alzheimer's Drug Leads

作者：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

来源：Journal of Medicinal Chemistry, 2011, 54(24): 8373-8385.

DOI：10.1021/jm201181f

We have identified highly selective imidazopyridines armed with benzimidazol and/or arylimidazole as potent beta-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 (K-I) 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 isophthalic 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 (K-I = 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.

• 出版日期2011-12-22
• 单位河北医科大学