Synthesis of 4-thiophen-2'-yl-1,4-dihydropyridines as potentiators of the CFTR chloride channel.
The gating of the CFTR chloride channel is altered by a group of mutations that cause cystic fibrosis. This gating defect may be corrected by small molecules called potentiators. Some 1,4-dihydropyridine (DHP) derivatives, bearing a thiophen-2-yl and a furanyl ring at the 4-position of the nucleus, were prepared and tested as CFTR potentiators. In particular, we evaluated the ability of novel DHPs to enhance the activity of the rescued DeltaF508-CFTR as measured with a functional assay based on the halide-sensitive yellow fluorescent protein. Most DHPs showed an effect comparable to or better than that of the reference compound genistein. The potency was instead significantly improved, with some compounds, such as 3g, 3h, 3n, 4a, 4b, and 4d, having a half effective concentration in the submicromolar range. CoMFA analysis gave helpful suggestions to improve the activity of DHPs.
Cateni
Francesca
F
Department of Pharmaceutical Sciences, Piazzale Europa 1, 34127 Trieste, Italy.
Zacchigna
Marina
M
Pedemonte
Nicoletta
N
Galietta
Luis J V
LJ
Mazzei
Marco T
MT
Fossa
Paola
P
Giampieri
Michele
M
Mazzei
Mauro
M
D000818:Animals; D002460:Cell Line; D003550:Cystic Fibrosis / Q000188:drug therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000819:agonists / Q000378:metabolism*; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008856:Microscopy, Fluorescence; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D004095:Dihydropyridines; D013876:Thiophenes; D019005:Cystic Fibrosis Transmembrane Conductance Regulator