Isoxazolopyrimidines as novel F508-CFTR correctors

Gui Jun Yu, Baoxue Yang, A. S. Verkman, Mark J. Kurth

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 F508-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 F508-CFTR cells.

Original languageEnglish (US)
Pages (from-to)1063-1066
Number of pages4
JournalSynlett
Issue number7
DOIs
StatePublished - 2010

Fingerprint

Pyrimidines
Nitriles
Cycloaddition
Chlorination
Mutant Proteins
Oxides
Substitution reactions
Sodium
Throughput
Molecules
pyrimidine

Keywords

  • Corrector
  • Cystic fibrosis
  • F508-CFTR
  • Isoxazolopyrimidine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Yu, G. J., Yang, B., Verkman, A. S., & Kurth, M. J. (2010). Isoxazolopyrimidines as novel F508-CFTR correctors. Synlett, (7), 1063-1066. https://doi.org/10.1055/s-0029-1219781

Isoxazolopyrimidines as novel F508-CFTR correctors. / Yu, Gui Jun; Yang, Baoxue; Verkman, A. S.; Kurth, Mark J.

In: Synlett, No. 7, 2010, p. 1063-1066.

Research output: Contribution to journalArticle

Yu, GJ, Yang, B, Verkman, AS & Kurth, MJ 2010, 'Isoxazolopyrimidines as novel F508-CFTR correctors', Synlett, no. 7, pp. 1063-1066. https://doi.org/10.1055/s-0029-1219781
Yu, Gui Jun ; Yang, Baoxue ; Verkman, A. S. ; Kurth, Mark J. / Isoxazolopyrimidines as novel F508-CFTR correctors. In: Synlett. 2010 ; No. 7. pp. 1063-1066.
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