Synthesis and structure-activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis

Emanuela Pesce, Marta Bellotti, Nara Liessi, Sara Guariento, Gianluca Damonte, Elena Cichero, Andrea Galatini, Annalisa Salis, Ambra Gianotti, Nicoletta Pedemonte, Olga Zegarra-Moran, Paola Fossa, Luis J V Galietta, Enrico Millo

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Abstract The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel present in the membrane of epithelial cells. Mutations affecting the CFTR gene cause cystic fibrosis (CF), a multi-organ severe disease. The most common CF mutation, F508del, impairs the processing and activity (gating) of CFTR protein. Other mutations, like G551D, only cause a gating defect. Processing and gating defects can be targeted by small molecules called generically correctors and potentiators, respectively. Aminoarylthiazoles (AATs) represent an interesting class of compounds that includes molecules with dual activity, as correctors and potentiators. With the aim to improve the activity profile of AATs, we have now designed and synthesized a library of novel compounds in order to establish an initial SAR that may provide indications about the chemical groups that are beneficial or detrimental for rescue activity. The new compounds were tested as correctors and potentiators in CFBE41o-expressing F508del-CFTR using a functional assay. A dual active compound, AAT-4a, characterized by improved efficacy and marked synergy when combined with the corrector VX-809 has been identified. Moreover, by computational methods, a possible binding site for AATs in nucleotide binding domain NBD1 has been detected. These results will direct the synthesis of new analogues with possibly improved activity.

Original languageEnglish
Article number7909
Pages (from-to)14-35
Number of pages22
JournalEuropean Journal of Medicinal Chemistry
Volume99
DOIs
Publication statusPublished - Jun 1 2015

Fingerprint

Cystic Fibrosis Transmembrane Conductance Regulator
Structure-Activity Relationship
Cystic Fibrosis
Chlorides
Derivatives
Defects
Mutation
Chloride Channels
Molecules
Regulator Genes
Processing
Computational methods
Libraries
Assays
Nucleotides
Genes
Epithelial Cells
Binding Sites
Membranes
Proteins

Keywords

  • AminoArylthiazole
  • CFTR
  • Corrector
  • Cystic fibrosis
  • Docking
  • SAR

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Synthesis and structure-activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis. / Pesce, Emanuela; Bellotti, Marta; Liessi, Nara; Guariento, Sara; Damonte, Gianluca; Cichero, Elena; Galatini, Andrea; Salis, Annalisa; Gianotti, Ambra; Pedemonte, Nicoletta; Zegarra-Moran, Olga; Fossa, Paola; Galietta, Luis J V; Millo, Enrico.

In: European Journal of Medicinal Chemistry, Vol. 99, 7909, 01.06.2015, p. 14-35.

Research output: Contribution to journalArticle

Pesce, E, Bellotti, M, Liessi, N, Guariento, S, Damonte, G, Cichero, E, Galatini, A, Salis, A, Gianotti, A, Pedemonte, N, Zegarra-Moran, O, Fossa, P, Galietta, LJV & Millo, E 2015, 'Synthesis and structure-activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis', European Journal of Medicinal Chemistry, vol. 99, 7909, pp. 14-35. https://doi.org/10.1016/j.ejmech.2015.05.030
Pesce, Emanuela ; Bellotti, Marta ; Liessi, Nara ; Guariento, Sara ; Damonte, Gianluca ; Cichero, Elena ; Galatini, Andrea ; Salis, Annalisa ; Gianotti, Ambra ; Pedemonte, Nicoletta ; Zegarra-Moran, Olga ; Fossa, Paola ; Galietta, Luis J V ; Millo, Enrico. / Synthesis and structure-activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis. In: European Journal of Medicinal Chemistry. 2015 ; Vol. 99. pp. 14-35.
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AU - Guariento, Sara

AU - Damonte, Gianluca

AU - Cichero, Elena

AU - Galatini, Andrea

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AU - Gianotti, Ambra

AU - Pedemonte, Nicoletta

AU - Zegarra-Moran, Olga

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N2 - Abstract The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel present in the membrane of epithelial cells. Mutations affecting the CFTR gene cause cystic fibrosis (CF), a multi-organ severe disease. The most common CF mutation, F508del, impairs the processing and activity (gating) of CFTR protein. Other mutations, like G551D, only cause a gating defect. Processing and gating defects can be targeted by small molecules called generically correctors and potentiators, respectively. Aminoarylthiazoles (AATs) represent an interesting class of compounds that includes molecules with dual activity, as correctors and potentiators. With the aim to improve the activity profile of AATs, we have now designed and synthesized a library of novel compounds in order to establish an initial SAR that may provide indications about the chemical groups that are beneficial or detrimental for rescue activity. The new compounds were tested as correctors and potentiators in CFBE41o-expressing F508del-CFTR using a functional assay. A dual active compound, AAT-4a, characterized by improved efficacy and marked synergy when combined with the corrector VX-809 has been identified. Moreover, by computational methods, a possible binding site for AATs in nucleotide binding domain NBD1 has been detected. These results will direct the synthesis of new analogues with possibly improved activity.

AB - Abstract The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel present in the membrane of epithelial cells. Mutations affecting the CFTR gene cause cystic fibrosis (CF), a multi-organ severe disease. The most common CF mutation, F508del, impairs the processing and activity (gating) of CFTR protein. Other mutations, like G551D, only cause a gating defect. Processing and gating defects can be targeted by small molecules called generically correctors and potentiators, respectively. Aminoarylthiazoles (AATs) represent an interesting class of compounds that includes molecules with dual activity, as correctors and potentiators. With the aim to improve the activity profile of AATs, we have now designed and synthesized a library of novel compounds in order to establish an initial SAR that may provide indications about the chemical groups that are beneficial or detrimental for rescue activity. The new compounds were tested as correctors and potentiators in CFBE41o-expressing F508del-CFTR using a functional assay. A dual active compound, AAT-4a, characterized by improved efficacy and marked synergy when combined with the corrector VX-809 has been identified. Moreover, by computational methods, a possible binding site for AATs in nucleotide binding domain NBD1 has been detected. These results will direct the synthesis of new analogues with possibly improved activity.

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