ArticleChemistry (Weinheim an der Bergstrasse, Germany)2019
Evaluation of 1,2,3-Triazoles as Amide Bioisosteres In Cystic Fibrosis Transmembrane Conductance Regulator Modulators VX-770 and VX-809.
Article in Chemistry (Weinheim an der Bergstrasse, Germany), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
9 citing papers in PubMed, 31 citations in OpenAlex.
- Probing Isosteric Replacement for Immunoadjuvant Design: Bis-Aryl Triazole Trehalolipids are Mincle Agonists.ACS medicinal chemistry letters · 2024Article
- Overview of CFTR activators and their recent studies for dry eye disease: a review.RSC medicinal chemistry · 2023Review
- Computational Exploration of Potential CFTR Binding Sites for Type I Corrector Drugs.Biochemistry · 2023Article
- Additive Potentiation of R334W-CFTR Function by Novel Small Molecules.Journal of personalized medicine · 2023Article
- Click Chemistry of Selenium Dihalides: Novel Bicyclic Organoselenium Compounds Based on Selenenylation/Bis-Functionalization Reactions and Evaluation of Glutathione Peroxidase-like Activity.International journal of molecular sciences · 2022Article
- Structure-Based Bioisosterism Design, Synthesis, Biological Evaluation and In Silico Studies of Benzamide Analogs as Potential Anthelmintics.Molecules (Basel, Switzerland) · 2022Article
- Journey on VX-809-Based Hybrid Derivatives towards Drug-like F508del-CFTR Correctors: From Molecular Modeling to Chemical Synthesis and Biological Assays.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Preparation of Acidic 5-Hydroxy-1,2,3-triazoles via the Cycloaddition of Aryl Azides with β-Ketoesters.The Journal of organic chemistry · 2021Article
- A New PqsR Inverse Agonist Potentiates Tobramycin Efficacy to Eradicate Pseudomonas aeruginosa Biofilms.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2021Article
Corrections and comments
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Authors and funding
16 authors at 3 institutions in 1 country.
Funding
Abstract
The 1,2,3-triazole has been successfully utilized as an amide bioisostere in multiple therapeutic contexts. Based on this precedent, triazole analogues derived from VX-809 and VX-770, prominent amide-containing modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), were synthesized and evaluated for CFTR modulation. Triazole 11, derived from VX-809, displayed markedly reduced efficacy in F508del-CFTR correction in cellular TECC assays in comparison to VX-809. Surprisingly, triazole analogues derived from potentiator VX-770 displayed no potentiation of F508del, G551D, or WT-CFTR in cellular Ussing chamber assays. However, patch clamp analysis revealed that triazole 60 potentiates WT-CFTR similarly to VX-770. The efficacy of 60 in the cell-free patch clamp experiment suggests that the loss of activity in the cellular assay could be due to the inability of VX-770 triazole derivatives to reach the CFTR binding site. Moreover, in addition to the negative impact on biological activity, triazoles in both structural classes displayed decreased metabolic stability in human microsomes relative to the analogous amides. In contrast to the many studies that demonstrate the advantages of using the 1,2,3-triazole, these findings highlight the negative impacts that can arise from replacement of the amide with the triazole and suggest that caution is warranted when considering use of the 1,2,3-triazole as an amide bioisostere.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.