Article ; Online: Synthesis and Evaluation of Ivacaftor Derivatives with Reduced Lipophilicity.
ACS omega
2023 Volume 8, Issue 48, Page(s) 45606–45615
Abstract: 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 ... ...
| Abstract | 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 |
|---|---|
| Language | English |
| Publishing date | 2023-11-25 |
| Publishing country | United States |
| Document type | Journal Article |
| ISSN | 2470-1343 |
| ISSN (online) | 2470-1343 |
| DOI | 10.1021/acsomega.3c05839 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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