Synthesis and Evaluation of Ivacaftor Derivatives with Reduced Lipophilicity

Mutations in the
unique ATP-binding cassette anion channel, the
cystic fibrosis conductance regulator (CFTR), lead to the inherited
fatal disease known as cystic fibrosis (CF). Ivacaftor enhances channel
gating of CFTR by stabilizing its open state and has been approved
as monotherapy for CF patients with CFTR gating mutations (e.g., G551D)
and as part of combination therapy with lumacaftor for CFTR folding
mutations (e.g., ΔF508). However, in the latter context, ivacaftor
may destabilize folding-rescued ΔF508-CFTR and membrane-associated
proteins and attenuate lumacaftor pharmacotherapy. Here, we tested
the hypothesis that the high lipophilicity of ivacaftor may contribute
to this effect. We describe the synthesis of three glutamic acid ivacaftor
derivatives with reduced lipophilicity that bear different charges
at neutral pH (compounds 2, 3, 4). In a cellular ion flux assay, all three restored G551D-CFTR channel
activity at comparable or better levels than ivacaftor. Furthermore,
unlike ivacaftor, compound 3 did not attenuate levels
of folding-rescued ΔF508 at the cell surface. Molecular modeling
predicts that the increased polarity of compound 3 allows
engagement with polar amino acids present in the binding pocket with
hydrogen bonding and ionic interactions, which are collectively higher
in strength as compared to hydrophobic interactions that stabilize
ivacaftor. Overall, the data suggests that reduced lipophilicity may
improve the efficacy of this class of CFTR potentiators when used
for folding-rescued ΔF508-CFTR.