title: Isoxazolopyrimidines as Novel ΔF508-CFTR Correctors.
abstract: Using a cell-based high-throughput screen, we identified isoxazolo[5,4-d]pyrimidines as novel small-molecule correctors of the cystic fibrosis mutant protein ΔF508-CFTR. 22 Isoxazolo[5,4-d]pyrimidine analogues were synthesized and tested. Synthesis of the key intermediate, 5-amino-3-arylisoxazole-4-carboxamide, was accomplished by nitrile oxide cycloaddition to (2-amino-1-cyano-2-oxoethyl)sodium. Formation of 3-arylisoxazolo-[5,4-d]pyrimidin-4(5H)-one and chlorination gave 4-chloro-3-arylisoxazolo[5,4-d]pyrimidine. Finally, functionalization at C-4 of the pyrimidine ring by nucleophilic substitution gave the targeted isoxazolo[5,4-d]pyrimidines. Six of the reported analogues had low micromolar potency for increasing halide transport in ΔF508-CFTR cells.
authors.affiliation: Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: Gui Jun
authors.initials: GJ
authors.lastname: Yu
authors.forename: Baoxue
authors.initials: B
authors.lastname: Yang
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kurth
keywords: corrector; cystic fibrosis; isoxazolopyrimidine; ΔF508-CFTR