The 1,2,3-triazole has been widely used as an amide bioisostere in a variety of drug discovery contexts. Oftentimes, use of the 1,2,3-triazole bioisostere provides similar or improved bioactivity and increased metabolic stability relative to the parent amide compound. In contrast, our application of the 1,2,3-triazole bioisostere strategy with the amide-containing drugs cystic fibrosis drugs VX-809 and VX-770 produced detrimental effects on bioactivity. Moreover, in some cases, the triazole decreased metabolic stability in human microsomes assays. Intrigued by these observations, we utilized X-ray crystallography and computational studies to investigate the structural consequences of replacing the amide with the triazole. These studies revealed subtle spatial and electronic differences between the amide and 1,2,3-triazole analogs. The lessons learned in the context of the cystic fibrosis drugs VX-809 and VX-770 could help inform medicinal chemists considering the use of the 1,2,3-triazole bioisostere.

Lessons learned from use of the 1,2,3-triazole as an amide bioisostere in cystic fibrosis drugs VX-809 and VX-770

ACS Fall 2021

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