Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
ChemMedChem ; 18(14): e202300145, 2023 07 17.
Article in English | MEDLINE | ID: mdl-37170841

ABSTRACT

Flupirtine and retigabine were essential drugs to combat pain and epilepsy. However, the Kv 7 potassium channel openers are fraught with hepatotoxicity and tissue discoloration, respectively, limiting their therapeutic value. Both adverse events are likely due to reactive metabolites arising from oxidative metabolism. Designing safer analogues lacking the structural elements leading to described side effects is an active area of current research. One of the main metabolites of flupirtine is the biologically inactive 4-fluorohippuric acid. Hitherto unexplained, the proposed metabolic pathway leading to the formation of 4-fluorohippuric acid from flupirtine is verified here. Through the use of eighteen flupirtine analogues, mechanistic details of this pathway could be elucidated. A possible connection with the in vitro hepatotoxicity of the flupirtine analogues and the levels of 4-fluorobenzoic acid formed in enzyme incubations was examined by correlation analysis. These findings provide important information for the design of new flupirtine analogues as potential drug candidates.


Subject(s)
Chemical and Drug Induced Liver Injury , Esterases , Humans , Analgesics/pharmacology , Aminopyridines/toxicity , Aminopyridines/chemistry , Structure-Activity Relationship
2.
ChemMedChem ; 10(2): 368-79, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25392984

ABSTRACT

Openers of neuronal voltage-gated potassium channels (KV ) are of interest as therapeutic agents for treating pain (flupirtine) and epilepsy (retigabine). In an effort to better understand the mechanisms of action and toxicity of flupirtine, we synthesized nine novel analogues with varying redox behavior. Flupirtine can be oxidatively metabolized into azaquinone diimines; thus, the oxidation potentials of flupirtine and its analogues were measured by cyclic voltammetry. KV 7.2/3 (KCNQ2/3) opening activity was determined by an established assay with HEK293 cells overexpressing these channels. A link was found between the oxidation potentials of the compounds and their EC50 values for potassium channel opening activity. On the other hand, no correlation was observed between oxidation potentials and cytotoxicity in cultures of transgenic mouse hepatocytes (TAMH). These results support the idea that oxidative metabolites of flupirtine contribute to the mechanism of action, similar to what was recently proposed for acetaminophen (paracetamol), but not to hepatotoxicity.


Subject(s)
Aminopyridines/chemistry , Analgesics/chemistry , KCNQ Potassium Channels/metabolism , Aminopyridines/analysis , Aminopyridines/toxicity , Analgesics/analysis , Analgesics/toxicity , Animals , Cell Line , Cell Survival/drug effects , Electrochemical Techniques , HEK293 Cells , Hepatocytes/cytology , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , KCNQ Potassium Channels/genetics , Mice , Mice, Transgenic , Nitrogen/chemistry , Oxidation-Reduction , Structure-Activity Relationship , Transforming Growth Factor alpha/genetics , Transforming Growth Factor alpha/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...