Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489, Greifswald, Germany.
ChemMedChem. 2022 Aug 17;17(16):e202200262. doi: 10.1002/cmdc.202200262. Epub 2022 Jul 7.
The K 7 potassium channel openers flupirtine and retigabine have been valuable options in the therapy of pain and epilepsy. However, as a result of adverse reactions, both drugs are currently no longer in therapeutic use. The flupirtine-induced liver injury and the retigabine linked tissue discolouration do not appear related at first glance; nevertheless, both events can be attributed to the triaminoaryl scaffold, which is affected by oxidation leading to elusive reactive quinone diimine or azaquinone diimine metabolites. Since the mechanism of action, i. e. K 7 channel opening, seems not to be involved in toxicity, this study aimed to further develop safer replacements for flupirtine and retigabine. In a ligand-based design strategy, replacing amino substituents of the triaminoaryl core with alkyl substituents led to carba analogues with improved oxidation resistance and negligible risk of quinoid metabolite formation. In addition to these improved safety features, some of the novel analogues exhibited significantly improved K 7.2/3 channel opening activity, indicated by an up to 13-fold increase in potency and an efficacy of up to 176 % compared to flupirtine, thus being attractive candidates for further development.
K7 钾通道开放剂氟吡汀和瑞替加滨在疼痛和癫痫的治疗中是非常有价值的选择。然而，由于不良反应，这两种药物目前已不再用于治疗。氟吡汀引起的肝损伤和瑞替加滨相关的组织变色乍一看似乎没有关联；然而，这两种事件都可以归因于三氨基芳基支架，该支架受到氧化的影响，导致难以捉摸的反应性醌二亚胺或氮杂醌二亚胺代谢物。由于作用机制（即 K7 通道开放）似乎与毒性无关，因此本研究旨在进一步开发更安全的氟吡汀和瑞替加滨替代品。在基于配体的设计策略中，用烷基取代基取代三氨基芳基核中的氨基取代基，导致碳正离子类似物具有更好的抗氧化性，几乎没有形成醌型代谢物的风险。除了这些改进的安全性特征外，一些新型类似物表现出显著改善的 K7.2/3 通道开放活性，与氟吡汀相比，效力提高了 13 倍，效力高达 176%，因此是进一步开发的有吸引力的候选药物。
