title: 3-(2-Benzyloxyphenyl)isoxazoles and isoxazolines: synthesis and evaluation as CFTR activators.
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.
authors.affiliation: Department of Chemistry, University of California, Davis, CA 95616-5295, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Sammelson
authors.forename: T
authors.initials: T
authors.lastname: Ma
authors.forename: Luis J V
authors.initials: LJ
authors.lastname: Galietta
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kurth
mesh_terms: D000478:Alkylation; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001711:Biotransformation / Q000187:drug effects; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D007202:Indicators and Reagents; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D009154:Mutation / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship
chemical_list: D007202:Indicators and Reagents; D007555:Isoxazoles; D019005:Cystic Fibrosis Transmembrane Conductance Regulator