Design, synthesis, and qualitative structure-activity evaluations of novel β-secretase inhibitors as potential Alzheimer's drug leads

Taleb H. Al-Tel, Mohammad H. Semreen, Raed A. Al-Qawasmeh, Marco F. Schmidt, Raafat El-Awadi, Mustafa Ardah, Rania Zaarour, Shashidhar N. Rao, Omar Ali El-Agnaf

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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 (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 iso-phthalic acid I. Of the most potent compounds, 34 displayed an IC 50 for BACE1 of 18 nM and exhibited cellular activity with an EC 50 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. (Figure presented)

Original languageEnglish
Pages (from-to)8373-8385
Number of pages13
JournalJournal of Medicinal Chemistry
Volume54
Issue number24
DOIs
Publication statusPublished - 22 Dec 2011
Externally publishedYes

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Amyloid Precursor Protein Secretases
Aspartic Acid Proteases
Ligands
Enzyme-Linked Immunosorbent Assay
Pharmaceutical Preparations
Enzymes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

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.; Ali El-Agnaf, Omar.

In: Journal of Medicinal Chemistry, Vol. 54, No. 24, 22.12.2011, p. 8373-8385.

Research output: Contribution to journalArticle

Al-Tel, Taleb H. ; Semreen, Mohammad H. ; Al-Qawasmeh, Raed A. ; Schmidt, Marco F. ; El-Awadi, Raafat ; Ardah, Mustafa ; Zaarour, Rania ; Rao, Shashidhar N. ; Ali El-Agnaf, Omar. / Design, synthesis, and qualitative structure-activity evaluations of novel β-secretase inhibitors as potential Alzheimer's drug leads. In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 24. pp. 8373-8385.
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