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

• DOI: 10.1016/j.ejmech.2015.05.030
• Publication Date: 2015-05-28T22:34:22Z
• Authors: 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
• Keywords: Models, Molecular; Protein Structure; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Chemistry Techniques, Synthetic; Cystic fibrosis; AminoArylthiazole; Corrector; Docking; Cell Line; Structure-Activity Relationship; 03 medical and health sciences; Chlorides; Models; AminoArylthiazole; CFTR; Corrector; Cystic fibrosis; Docking; SAR; Biological Transport; Cell Line; Chemistry Techniques, Synthetic; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Ion Channel Gating; Models, Molecular; Mutation; Protein Structure, Tertiary; Structure-Activity Relationship; Thiazoles; Drug Design; Pharmacology; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry; Humans; CFTR; Pharmacology; 0303 health sciences; AminoArylthiazole; CFTR; Corrector; Cystic fibrosis; Docking; SAR; Drug Discovery3003 Pharmaceutical Science; Synthetic; Organic Chemistry; Molecular; Biological Transport; Chemistry Techniques; Protein Structure, Tertiary; 3. Good health; Thiazoles; Drug Design; Mutation; Ion Channel Gating; Tertiary; SAR

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.