title: Synthesis and structure-activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis.
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.
authors.affiliation: Istituto Giannina Gaslini, via Gerolamo Gaslini 5, 16147 Genoa, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pesce
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, Italy; Center of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV 5, 16132 Genoa, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Bellotti
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, Italy.
authors.forename: Nara
authors.initials: N
authors.lastname: Liessi
authors.affiliation: Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Guariento
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, Italy; Center of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV 5, 16132 Genoa, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Damonte
authors.affiliation: Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cichero
authors.affiliation: Department of Chemistry and Industrial Chemistry, University of Genoa, Via Dodecaneso 31, 16146 Genoa, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Galatini
authors.affiliation: Center of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV 5, 16132 Genoa, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Salis
authors.affiliation: Istituto Giannina Gaslini, via Gerolamo Gaslini 5, 16147 Genoa, Italy.
authors.forename: Ambra
authors.initials: A
authors.lastname: Gianotti
authors.affiliation: Istituto Giannina Gaslini, via Gerolamo Gaslini 5, 16147 Genoa, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Pedemonte
authors.affiliation: Istituto Giannina Gaslini, via Gerolamo Gaslini 5, 16147 Genoa, Italy.
authors.forename: Olga
authors.initials: O
authors.lastname: Zegarra-Moran
authors.affiliation: Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.affiliation: Istituto Giannina Gaslini, via Gerolamo Gaslini 5, 16147 Genoa, Italy.
authors.forename: Luis J V
authors.initials: LJ
authors.lastname: Galietta
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, Italy; Center of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV 5, 16132 Genoa, Italy. Electronic address: enrico.millo@unige.it.
authors.forename: Enrico
authors.initials: E
authors.lastname: Millo
mesh_terms: D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D060326:Chemistry Techniques, Synthetic; D002712:Chlorides / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008958:Models, Molecular; D009154:Mutation; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D002712:Chlorides; D013844:Thiazoles; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: AminoArylthiazole; CFTR; Corrector; Cystic fibrosis; Docking; SAR