The search for a common structural moiety among selected pharmacological correctors of the mutant CFTR chloride channel

Erika Nieddu, Benedetta Pollarolo, Marco T. Mazzei, Maria Anzaldi, Silvia Schenone, Nicoletta Pedemonte, Emanuela Pesce, Luis J V Galietta, Mauro Mazzei

Research output: Contribution to journalArticle

Abstract

Background: The F508del mutation impairs the trafficking of CFTR from endoplasmic reticulum to plasma membrane and is responsible of a severe form of cystic fibrosis. Trafficking can be improved by small organic molecules called 'correctors'. Materials & methods: By different synthetic ways, we prepared 4-chloroanisole and 2-(4-chloroanisol-2-yl)aminothiazole derivatives. Such compounds were ineffective as correctors but we could find a sign of activity in an intermediate. In the meantime, we found a common pharmacophoric moiety present in four known correctors. Results: Following this structural indication, we synthesized a small set of new molecules endowed with a significant, even if not great, F508del-CFTR rescue activity. Conclusion: The cited structural feature seems interesting in the search of new correctors. To corroborate this observation, later on we found a new pyrazine derivative (Novartis) endowed with a potent activity as corrector and having the cited common design.

Original languageEnglish
Pages (from-to)1857-1868
Number of pages12
JournalFuture Medicinal Chemistry
Volume6
Issue number17
DOIs
Publication statusPublished - Nov 1 2014

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Molecular Medicine
  • Medicine(all)

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    Nieddu, E., Pollarolo, B., Mazzei, M. T., Anzaldi, M., Schenone, S., Pedemonte, N., Pesce, E., Galietta, L. J. V., & Mazzei, M. (2014). The search for a common structural moiety among selected pharmacological correctors of the mutant CFTR chloride channel. Future Medicinal Chemistry, 6(17), 1857-1868. https://doi.org/10.4155/fmc.14.118