Evaluation of 1,2,3-Triazoles as Amide Bioisosteres In Cystic Fibrosis Transmembrane Conductance Regulator Modulators VX-770 and VX-809

Jake E Doiron; Christina A Le; Britton K Ody; Jonathon B Brace; Savannah J Post; Nathan L Thacker; Harrison M Hill; Gary W Breton; Matthew J Mulder; Sichen Chang; Thomas M Bridges; Liping Tang; Wei Wang; Steven M Rowe; Stephen G Aller; Mark Turlington

doi:10.1002/chem.201805919

Evaluation of 1,2,3-Triazoles as Amide Bioisosteres In Cystic Fibrosis Transmembrane Conductance Regulator Modulators VX-770 and VX-809

Chemistry. 2019 Mar 7;25(14):3662-3674. doi: 10.1002/chem.201805919. Epub 2019 Feb 11.

Authors

Jake E Doiron¹, Christina A Le², Britton K Ody¹, Jonathon B Brace¹, Savannah J Post¹, Nathan L Thacker¹, Harrison M Hill¹, Gary W Breton¹, Matthew J Mulder³, Sichen Chang³, Thomas M Bridges³, Liping Tang^{4

5}, Wei Wang^{5

6}, Steven M Rowe^{4

5

6}, Stephen G Aller², Mark Turlington¹

Affiliations

¹ Department of Chemistry and Biochemistry, Berry College, Mount Berry, Georgia, 30165, USA.
² Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama, 35205, USA.
³ Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee, 37232, USA.
⁴ Departments of Medicine and Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, 35205, USA.
⁵ Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, 35205, USA.
⁶ Department of Cell, Development, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, 35205, USA.

Abstract

The 1,2,3-triazole has been successfully utilized as an amide bioisostere in multiple therapeutic contexts. Based on this precedent, triazole analogues derived from VX-809 and VX-770, prominent amide-containing modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), were synthesized and evaluated for CFTR modulation. Triazole 11, derived from VX-809, displayed markedly reduced efficacy in F508del-CFTR correction in cellular TECC assays in comparison to VX-809. Surprisingly, triazole analogues derived from potentiator VX-770 displayed no potentiation of F508del, G551D, or WT-CFTR in cellular Ussing chamber assays. However, patch clamp analysis revealed that triazole 60 potentiates WT-CFTR similarly to VX-770. The efficacy of 60 in the cell-free patch clamp experiment suggests that the loss of activity in the cellular assay could be due to the inability of VX-770 triazole derivatives to reach the CFTR binding site. Moreover, in addition to the negative impact on biological activity, triazoles in both structural classes displayed decreased metabolic stability in human microsomes relative to the analogous amides. In contrast to the many studies that demonstrate the advantages of using the 1,2,3-triazole, these findings highlight the negative impacts that can arise from replacement of the amide with the triazole and suggest that caution is warranted when considering use of the 1,2,3-triazole as an amide bioisostere.

Keywords: bioisosteres; corrector; cystic fibrosis; potentiators; triazole.

Abstract

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