Synthesis of 4-thiophen-2′-yl-1,4-dihydropyridines as potentiators of the CFTR chloride channel

被引：27

作者：

Cateni, Francesca ^{[2
]}

Zacchigna, Marina ^{[2
]}

Pedemonte, Nicoletta ^{[3
]}

Galietta, Luis J. V. ^{[3
]}

Mazzei, Marco T. ^{[4
]}

Fossa, Paola ^{[1
]}

Giampieri, Michele ^{[1
]}

Mazzei, Mauro ^{[1
]}

机构：

[1] Dept Pharmaceut Sci, I-16132 Genoa, Italy

[2] Dept Pharmaceut Sci, I-34127 Trieste, Italy

[3] Ist Giannina Gaslini, Mol Genet Lab, I-16147 Genoa, Italy

[4] Dept Expt Med, I-16132 Genoa, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2009年 / 17卷 / 23期

关键词：

Cystic fibrosis; CFTR; Dihydropyridine; Potentiators; CoMFA; TRANSMEMBRANE CONDUCTANCE REGULATOR; NUCLEOTIDE-BINDING DOMAINS; SMALL-MOLECULE CORRECTORS; CYSTIC-FIBROSIS; PROTEIN; 1,4-DIHYDROPYRIDINES; TRAFFICKING; ACTIVATORS; MUTATIONS; PROSPECTS;

D O I：

10.1016/j.bmc.2009.10.028

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 Delta F508-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. (c) 2009 Elsevier Ltd. All rights reserved.

引用

页码：7894 / 7903

页数：10

共 27 条

[1] The protease-antiprotease battle in the cystic fibrosis lung [J].