3-(2-Benzyloxyphenyl)isoxazoles and isoxazolines: synthesis and evaluation as CFTR activators.
Sammelson RE, Ma T, Galietta LJ, Verkman AS, Kurth MJ.
A novel class of activators for chloride conductance in the cystic fibrosis transmembrane conductance regulator (CFTR) protein has been identified. These 3-(2-benzyloxyphenyl)isoxazoles and 3-(2-benzyloxyphenyl)isoxazolines were synthesized employing the 1,3-dipolar cycloaddition of nitrile oxides with various alkene and alkyne dipolarophiles. Utilizing a fluorescence cell-based assay of halide transport, the best compounds increased CFTR-dependent chloride transport with half-maximal stimulation at 20-50 microM.