Cystic fibrosis (CF) is a lethal pulmonary disease caused by mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common CFTR mutation, deletion of phenylalanine at the 508<sup>th</sup> position (F508del), results in CFTR misfolding that causes significant protein degradation. VX-809 is a drug known to partially correct the misfolding of F508del-CFTR; however, better corrector drugs are needed for CF treatment. As a means to investigate the potential for generating improved correctors using the VX-809 scaffold as a starting point, the synthesis of 1,2,3-triazole analogs of VX-809 was explored. Synthesis of triazole analogs of VX-809 in which the central amide in VX-809 was replaced with the triazole bioisostere was accomplished via the copper-catalyzed azide-alkyne cycloaddition reaction. While triazole analogs of VX-809 displayed corrective activity in F508del-CFTR, the corrective activity was observed to be significantly decreased in comparison with VX-809. These findings suggest that the 1,2,3-triazole functionality is not optimal within the VX-809 structural framework.

Synthesis and biological evaluation of 1,2,3-triaozle analogs of CFTR corrector VX-809

2019 Spring National Meeting

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