Cystic fibrosis (CF) is a lethal lung disease caused by mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) protein that leads to loss of protein stability and/or function. VX-770 is an FDA-approved potentiator drug for the treatment of CF that combats CF by increasing the function of mutant forms of the CFTR protein. While VX-770 has revolutionized CF therapy, the search for additional CFTR potentiators remains a priority. In a variety of drug discovery projects, the substitution of amides with the bioisostereic 1,2,3-triazoles has been reported to increase potency and/or physiochemical properties of medicinal compounds. We report the synthesis of 1,2,3-triaozle analogs of VX-770 in which the amide bond present in VX-770 was replaced with the triazole bioisostere in order to determine if this substitution would be beneficial. The synthesis of triazole-containing VX-770 analogs required the use of a suitable nitrogen protecting group for the quinolin-4(1H)-one scaffold found in VX-770 due to the incompatibility of this moiety with the Cu-catalyzed azide-alkyne cycloaddition reaction. The development of a synthetic method to access triazole analogs of VX-770 has enabled evaluation of the suitability of the triazole as an amide bioisostere in this chemical scaffold.

Synthesis of 1,2,3-triazole analogs of CFTR potentiator VX-770

2019 Spring National Meeting

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