Replacing the oxidation‐sensitive triaminoaryl chemotype of problematic KV7 channel openers: Exploration of a nicotinamide scaffold. Issue 2 (17th November 2022)

• Record Type: Journal Article
• Authors: Wurm, Konrad W.; Bartz, Frieda‐Marie; Schulig, Lukas; Bodtke, Anja; Bednarski, Patrick J.; Link, Andreas
• Is Part Of: Archiv der Pharmazie. Volume 356:Issue 2(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-11-17
• Subjects: flupirtine -- KCNQ -- KV7 -- nicotinamide -- retigabine; Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.202200473
• Languages: English
• ISSNs: 0365-6233

Abstract

Abstract: KV 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 KV 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 KV 7.2/3 opening activity, as evidenced by EC50 values approaching the single‐digit nanomolar range. On the other hand, weighted KV 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. Abstract : A nicotinamide scaffold, which was developed as a replacement for the triaminoaryl‐type KV 7 openers flupirtine and retigabine to prevent the formation of quinoid metabolites, was successfully optimized in this work. By introducing an appropriate cyclic substituent and improving crucial ligand–lipid interactions, analog 18c was obtained, which is 150 times as potent as flupirtine in terms of KV 7.2/3 opening.