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

Hamadeh Tarazi; Raed Abu Odeh; Raed Al-Qawasmeh; Imad Abu Yousef; Wolfgang Voelter; Taleb H Al-Tel

doi:10.1016/j.ejmech.2016.11.021

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

Eur J Med Chem. 2017 Jan 5:125:1213-1224. doi: 10.1016/j.ejmech.2016.11.021. Epub 2016 Nov 12.

Authors

Hamadeh Tarazi¹, Raed Abu Odeh², Raed Al-Qawasmeh³, Imad Abu Yousef⁴, Wolfgang Voelter⁵, Taleb H Al-Tel⁶

Affiliations

¹ 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.
² 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.
³ Department of Chemistry, The University of Jordan, Amman 11942, Jordan.
⁴ College of Arts and Sciences, Department of Biology, Chemistry and Environmental Sciences, American University of Sharjah, Sharjah, United Arab Emirates.
⁵ Interfakultäres Institut für Biochemie, Eberhard-Karls-Universität Tübingen, Hoppe-Seyler-Straße 4, D-72076 Tübingen, Germany.
⁶ 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.

PMID: 27871037
DOI: 10.1016/j.ejmech.2016.11.021

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 IC₅₀ value 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 EC₅₀ value of 0.29 μM.

Keywords: Alzheimer's disease; Isophthalic acid derivatives; Molecular modeling; Structure activity relationship; Structure-based drug design; Transition state mimics; β-secretase inhibitors.

MeSH terms

Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / chemistry
Amyloid Precursor Protein Secretases / metabolism
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / chemistry
Aspartic Acid Endopeptidases / metabolism
Cell Line
Drug Design
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology
Molecular Docking Simulation
Phthalic Acids / chemical synthesis
Phthalic Acids / chemistry*
Phthalic Acids / pharmacology*
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Imidazoles
Phthalic Acids
isophthalate
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human