3-(2-Benzyloxyphenyl)isoxazoles and isoxazolines: synthesis and evaluation as CFTR activators

Robert E Sammelson; T Ma; Luis J V Galietta; A S Verkman; Mark J Kurth

doi:10.1016/s0960-894x(03)00482-7

3-(2-Benzyloxyphenyl)isoxazoles and isoxazolines: synthesis and evaluation as CFTR activators

Bioorg Med Chem Lett. 2003 Aug 4;13(15):2509-12. doi: 10.1016/s0960-894x(03)00482-7.

Authors

Robert E Sammelson¹, T Ma, Luis J V Galietta, A S Verkman, Mark J Kurth

Affiliation

¹ Department of Chemistry, University of California, Davis, CA 95616-5295, USA.

PMID: 12852954
DOI: 10.1016/s0960-894x(03)00482-7

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alkylation
Animals
Binding Sites / drug effects
Biotransformation / drug effects
Cystic Fibrosis Transmembrane Conductance Regulator / genetics
Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
Indicators and Reagents
Isoxazoles / chemical synthesis*
Isoxazoles / pharmacology*
Mutation / physiology
Rats
Rats, Inbred F344
Structure-Activity Relationship

Substances

Indicators and Reagents
Isoxazoles
Cystic Fibrosis Transmembrane Conductance Regulator