Pyrazolylthiazole as ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator Correctors with Improved Hydrophilicity Compared to Bithiazoles

被引：29

作者：

Ye, Long ^{[1
]}

Knapp, John M. ^{[1
]}

Sangwung, Panjamaporn ^{[2
]}

Fettinger, James C. ^{[1
]}

Verkman, A. S. ^{[2
]}

Kurth, Mark J. ^{[1
]}

机构：

[1] Univ Calif Davis, Dept Chem, Davis, CA 95616 USA

[2] Univ Calif San Francisco, Dept Physiol & Med, San Francisco, CA 94143 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 09期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

SMALL-MOLECULE CORRECTORS; CYSTIC-FIBROSIS; SOLUBILITY; CHLORIDE; DEFECTS; MODEL;

D O I：

10.1021/jm100235h

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Deletion of phenylalanine residue 508 (Delta F508) in the cystic fibrosis (CF) transmembrane conductance regulator protein (CFTR) is a major cause of CF. Small molecule "correctors" of defective A Delta 508-CFTR cellular processing hold promise for CF therapy. We previously identified and characterized bithiazole CF corrector 1 and s-cis-locked bithiazole 2. Herein, we report the regiodivergent synthesis of N gamma and N beta isomers of thiazole-tethered pyrazoles with improved hydrophilicity compared to bithiazoles. We synthesized a focused library of 54 pyrazolylthiazoles 3, which included examples of both regioisomers 4 and 5. The thiazole-tethered pyrazoles allowed incorporation of property-modulating functionality on the pyrazole ring (ester, acid, and amide) while retaining Delta F508-CFTR corrector activity (EC50) of under 1 mu M. The most active pyrazolylthiazole (14h) has an experimentally determined log P of 4.1, which is 1.2 log units lower than bithiazole CF corrector 1.

引用

页码：3772 / 3781

页数：10

共 30 条

[1] Cystic fibrosis: A worldwide analysis of CFTR mutations - Correlation with incidence data and application to screening [J].