Cystic Fibrosis (CF) is a devastating lung disease resulting from mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene that codes for the CFTR anion channel. Mutations to the CFTR gene cause deficits in protein folding, expression, and function. Ivacaftor (VX-770) is an FDA-approved drug that helps restore protein function by increasing the open probability (Po) of the CFTR channel. While VX-770 represents a landmark achievement in CF therapy, the development of improved drug therapies for CF remains a priority. Recently, the 1,2,3-triazole moiety has been successfully used as an amide bioisostere in many medicinal chemistry contexts. In many of these instances, use of the triazole improves drug potency and/or physiochemical properties, suggesting that the substitution of the amide in VX-770 with the 1,2,3-triazole could be beneficial. Here we describe the pharmacological analysis of VX-770 and its corresponding 1,2,3-triazole containing analog 1. Surprisingly, Ussing chamber analysis across several mutant CFTR cell lines reveals that 1 is unable to improve CFTR function in the cellular assay. However, patch clamp analysis reveals that triazole 1 had similar potency (5nM) to VX-770 (1nM) when exposed directly to the CFTR channel. This finding suggests that triazole 1 is a potent potentiator of CFTR but is unable to reach the CFTR binding site in a cellular system. The loss of activity of triazole analog 1 in the cellular assay provides an important example of the less reported adverse impacts of the 1,2,3-triazole and suggests that caution should be used when considering the use of the triazole as an amide bioisostere.

Pharmacological analysis of 1,2,3-triazoles as amide bioisosteres in potentiators of the cystic fibrosis transmembrane conductance regulator protein

2019 Spring National Meeting

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