Discovery of ethyl urea derivatives as inhibitors of islet amyloid polypeptide fibrillization and cytotoxicity.

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  • Additional Information
    • Source:
      Publisher: Canadian Science Publishing Country of Publication: Canada NLM ID: 0372712 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1205-7541 (Electronic) Linking ISSN: 00084212 NLM ISO Abbreviation: Can J Physiol Pharmacol Subsets: MEDLINE
    • Publication Information:
      Publication: 2011- : Ottawa, ON : Canadian Science Publishing
      Original Publication: Ottawa, National Research Council of Canada.
    • Subject Terms:
      Islet Amyloid Polypeptide/*antagonists & inhibitors ; Islet Amyloid Polypeptide/*metabolism ; Islets of Langerhans/*drug effects ; Urea/*analogs & derivatives; Amyloid/metabolism ; Amyloidosis/drug therapy ; Amyloidosis/metabolism ; Diabetes Mellitus, Type 2/metabolism ; Humans ; Islet Amyloid Polypeptide/adverse effects ; Islets of Langerhans/metabolism ; Small Molecule Libraries/pharmacology ; Urea/pharmacology
    • Abstract:
      Islet amyloid polypeptide (IAPP) has been shown to form amyloid deposits in pancreatic islets, thereby furthering type 2 diabetes disease progression. Further discovery of new molecules is needed to create a diverse set of molecules that impede pancreatic amyloidosis. We have recently designed and synthesized N-phenyl-N'-(2-ethyl)ureas (EU) that are non-cytotoxic small molecules, to evaluate the role of the aryl-substituted moiety on the inhibition of hIAPP fibrillization. Several EUs were tested in vitro for their anti-amyloidogenic activity using the fluorometric ThT assay, the photo-induced cross-linking (PIUCP) assay, and cell survival assay in pancreatic MIN-6 cells. EU-362 and EU-418 were able to significantly inhibit the formation of hIAPP fibrils and protected cells from amyloid cytotoxic effects. Our results suggest that increasing the nucleophilic potency of the aryl moiety significantly enhances the anti-amyloidogenic activity of the molecules.
    • Contributed Indexing:
      Keywords: IAPP; N-phenyl-N′-(2-ethyl)urea (EU); amyloid; amyloïde; diabetes; diabète; inhibiteurs de la fibrillisation; inhibitors of fibrillization
    • Accession Number:
      0 (Amyloid)
      0 (Islet Amyloid Polypeptide)
      0 (Small Molecule Libraries)
      7K14B03X18 (ethylurea)
      8W8T17847W (Urea)
    • Publication Date:
      Date Created: 20151219 Date Completed: 20161213 Latest Revision: 20220408
    • Publication Date:
      20221213
    • Accession Number:
      10.1139/cjpp-2015-0204
    • Accession Number:
      26679837