Arch Pharm (Weinheim)
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, Greifswald, Germany.
Published: February 2023
K 7 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 K 7 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 K 7.2/3 opening activity, as evidenced by EC values approaching the single-digit nanomolar range. On the other hand, weighted K 7.2/3 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.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1002/ardp.202200473 | DOI Listing |
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!
© LitMetric 2025. All rights reserved.