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[摘要]：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 Delta 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 Delta F508-CFTR cells. |
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