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 language | English |
|---|---|
| Article number | 7909 |
| Pages (from-to) | 14-35 |
| Number of pages | 22 |
| Journal | European Journal of Medicinal Chemistry |
| Volume | 99 |
| DOIs | |
| Publication status | Published - Jun 1 2015 |
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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 journal › Article
}
TY - JOUR
T1 - Synthesis and structure-activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis
AU - Pesce, Emanuela
AU - Bellotti, Marta
AU - Liessi, Nara
AU - Guariento, Sara
AU - Damonte, Gianluca
AU - Cichero, Elena
AU - Galatini, Andrea
AU - Salis, Annalisa
AU - Gianotti, Ambra
AU - Pedemonte, Nicoletta
AU - Zegarra-Moran, Olga
AU - Fossa, Paola
AU - Galietta, Luis J V
AU - Millo, Enrico
PY - 2015/6/1
Y1 - 2015/6/1
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.
KW - AminoArylthiazole
KW - CFTR
KW - Corrector
KW - Cystic fibrosis
KW - Docking
KW - SAR
UR - http://www.scopus.com/inward/record.url?scp=84930646286&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84930646286&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2015.05.030
DO - 10.1016/j.ejmech.2015.05.030
M3 - Article
C2 - 26041577
AN - SCOPUS:84930646286
VL - 99
SP - 14
EP - 35
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
M1 - 7909
ER -