The author of 《Sulfide analogues of flupirtine and retigabine with nanomolar KV7.2/KV7.3 channel opening activity》 were Bock, Christian; Surur, Abdrrahman S.; Beirow, Kristin; Kindermann, Markus K.; Schulig, Lukas; Bodtke, Anja; Bednarski, Patrick J.; Link, Andreas. And the article was published in ChemMedChem in 2019. Category: pyridine-derivatives The author mentioned the following in the article:
The potassium channel openers flupirtine and retigabine have proven to be valuable analgesics or antiepileptics. Their recent withdrawal due to occasional hepatotoxicity and tissue discoloration, resp., leaves a therapeutic niche unfilled. Metabolic oxidation of both drugs gives rise to the formation of electrophilic quinones. These elusive, highly reactive metabolites may induce liver injury in the case of flupirtine and blue tissue discoloration after prolonged intake of retigabine. We examined which structural features can be altered to avoid the detrimental oxidation of the aromatic ring and shift oxidation toward the formation of more benign metabolites. Structure-activity relationship studies were performed to evaluate the KV7.2/3 channel opening activity of 45 derivatives Sulfide analogs were identified that are devoid of the risk of quinone formation, but possess potent KV7.2/3 opening activity. For example, flupirtine analog 3-(3,5-difluorophenyl)-N-(6-(isobutylthio)-2-(pyrrolidin-1-yl)pyridin-3-yl)propanamide (48) has 100-fold enhanced activity (EC50=1.4 nM), a vastly improved toxicity/activity ratio, and the same efficacy as retigabine in vitro. In the experiment, the researchers used 2-(Bromomethyl)pyridine hydrobromide(cas: 31106-82-8Category: pyridine-derivatives)
2-(Bromomethyl)pyridine hydrobromide(cas: 31106-82-8) belongs to pyridine. Pyridine is very deactivated towards electrophilic substitution with respect to benzene. For this reason classical formylation, using methods such as the Gattermann or Vilsmeier reactions, are not generally successful. Category: pyridine-derivatives