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Replacing the oxidation‐sensitive triaminoaryl chemotype of problematic KV7 channel openers: Exploration of a nicotinamide scaffold
- KV7 channel openers have proven their therapeutic value in the treatment of pain as well as epilepsy and, moreover, they hold the potential to expand into additional indications with unmet medical needs. However, the clinically validated but meanwhile discontinued KV7 channel openers flupirtine and retigabine bear an oxidation‐sensitive triaminoraryl scaffold, which is suspected of causing adverse drug reactions via the formation of quinoid oxidation products. Here, we report the design and synthesis of nicotinamide analogs and related compounds that remediate the liability in the chemical structure of flupirtine and retigabine. Optimization of a nicotinamide lead structure yielded analogs with excellent KV7.2/3 opening activity, as evidenced by EC50 values approaching the single‐digit nanomolar range. On the other hand, weighted KV7.2/3 opening activity data including inactive compounds allowed for the establishment of structure–activity relationships and a plausible binding mode hypothesis verified by docking and molecular dynamics simulations.
Author: | Konrad W. Wurm, Frieda‐Marie Bartz, Lukas Schulig, Anja Bodtke, Patrick J. BednarskiORCiD, Andreas Link |
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URN: | urn:nbn:de:gbv:9-opus-83145 |
DOI: | https://doi.org/10.1002/ardp.202200473 |
ISSN: | 1521-4184 |
Parent Title (German): | Archiv der Pharmazie |
Publisher: | Wiley |
Place of publication: | Hoboken, NJ |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2022/11/17 |
Date of first Publication: | 2023/02/01 |
Release Date: | 2024/02/26 |
Tag: | KCNQ; KV7; flupirtine; nicotinamide; retigabine |
Volume: | 356 |
Issue: | 2 |
Article Number: | 2200473 |
Page Number: | 29 |
Faculties: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Pharmazie |
Collections: | weitere DFG-förderfähige Artikel |
Licence (German): | Creative Commons - Namensnennung 4.0 International |