title: Design, synthesis and SAR analysis of potent BACE1 inhibitors: Possible lead drug candidates for Alzheimer's disease.
abstract: We have identified potent isophthalic acid derivatives armed with imidazol and indolyl groups as potent β-secretase inhibitors. The most effective analogs demonstrated low nano-molar potency for the BACE1 (β-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 IC50value for BACE1 of 75 nM, and exhibited cellular activity with an EC50 value of 0.81 μM. On the other hand, compound 11b was found to be the most potent compound in the cell-based assay with an EC50value of 0.29 μM.
authors.affiliation: College of Pharmacy, University of Sharjah, PO Box 27272, Sharjah, United Arab Emirates; Sharjah Institute for Medical Research, University of Sharjah, PO Box 27272, Sharjah, United Arab Emirates.
authors.forename: Hamadeh
authors.initials: H
authors.lastname: Tarazi
authors.affiliation: Sharjah Institute for Medical Research, University of Sharjah, PO Box 27272, Sharjah, United Arab Emirates; College of Health Sciences, Department of Medical Laboratory Sciences, University of Sharjah, PO Box 27272, Sharjah, United Arab Emirates.
authors.forename: Raed Abu
authors.initials: RA
authors.lastname: Odeh
authors.affiliation: Department of Chemistry, The University of Jordan, Amman 11942, Jordan.
authors.forename: Raed
authors.initials: R
authors.lastname: Al-Qawasmeh
authors.affiliation: College of Arts and Sciences, Department of Biology, Chemistry and Environmental Sciences, American University of Sharjah, Sharjah, United Arab Emirates.
authors.forename: Imad Abu
authors.initials: IA
authors.lastname: Yousef
authors.affiliation: Interfakultäres Institut für Biochemie, Eberhard-Karls-Universität Tübingen, Hoppe-Seyler-Straße 4, D-72076 Tübingen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Voelter
authors.affiliation: College of Pharmacy, University of Sharjah, PO Box 27272, Sharjah, United Arab Emirates; Sharjah Institute for Medical Research, University of Sharjah, PO Box 27272, Sharjah, United Arab Emirates. Electronic address: taltal@sharjah.ac.ae.
authors.forename: Taleb H
authors.initials: TH
authors.lastname: Al-Tel
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D010795:Phthalic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D010795:Phthalic Acids; C059768:isophthalate; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer's disease; Isophthalic acid derivatives; Molecular modeling; Structure activity relationship; Structure-based drug design; Transition state mimics; β-secretase inhibitors