title: Design, synthesis, and qualitative structure-activity evaluations of novel β-secretase inhibitors as potential Alzheimer's drug leads.
abstract: We have identified highly selective imidazopyridines 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 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 (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.
authors: College of Pharmacy and Sharjah Institute for Medical Research, University of Sharjah, P.O. Box 27272, Sharjah, UAE. taltal@sharjah.ac.ae
authors: Taleb H
authors: TH
authors: Al-Tel
authors: Mohammad H
authors: MH
authors: Semreen
authors: Raed A
authors: RA
authors: Al-Qawasmeh
authors: Marco F
authors: MF
authors: Schmidt
authors: Raafat
authors: R
authors: El-Awadi
authors: Mustafa
authors: M
authors: Ardah
authors: Rania
authors: R
authors: Zaarour
authors: Shashidhar N
authors: SN
authors: Rao
authors: Omar
authors: O
authors: El-Agnaf
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D008024:Ligands; D011725:Pyridines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human