Project Details
Projekt
Identification of analogs that improve activity towards opened KV7.2/3-channels while reducing adverse effects on liver cells in vitro
Subject Area
Pharmacy
Organic Molecular Chemistry - Synthesis and Characterisation
Organic Molecular Chemistry - Synthesis and Characterisation
Term
from 2015 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 277978407
The structurally related potassium channel modulators flupirtine and retigabine were recalled recently from the market due to undesirable side effects. The cause for toxicity is likely to be due to the oxidation of both drugs to reactive metabolites, which in the case of flupirtine can cause liver damage and in the case of retigabine can react with endogenic melanin to form blue pigments in the eye and finger nail tissues. In the previous grant, we developed analogues of both flupirtine and retigabine, whereby a nitrogen was exchanged for a sulfur atom, resulting in analogues that are oxidized either to unreactive sulfoxides and sulfones or are inert to oxidations altogether. These analogues could offer the advantage that they will not be biotransformed to toxic azaquinonediimines metabolites; thus, neither reactions with proteins to form immunogenic haptens that could cause hepatotoxicity, nor reactions leading to the formation of color pigments are feared. At the same time, many of the newly synthesized analogues showed much improved potency with regards to opening of the heterotetrameric Kv7.2/3 channel. Thus, they could possibly be dosed at much lower levels than the original analgesic drug flupirtine or the antiepileptic drug retigabine, which after their removal from the market opened a vacant therapeutic niche. The main goal of the project is to explore the biological activities of new potassium channel modulators with respect to channel opening activity and toxicity in an iterative process of synthesis and screening aimed at improving the therapeutic potential of this unique class of drugs. Moreover, we wish to explore the unproven hypothesis that exchange of the nitrogen atoms for sulfur atom can result in an advantageous inhibition of oxidation or a metabolic switching to less toxic products.Moving forward it is important to assess the selectivity of the compounds for Kv7.2/3 by determining the activity on other ion channels. This could also lead to the discovery of new lead structures with uniquely different selectivity patterns. Furthermore, the oxidation properties should not only be evaluated with electrochemical methods, as we have done in the past, but more closely with biological systems so that the potential formation of reactive metabolites can be better anticipated. These studies will also serve to optimize the pharmacokinetic properties of the new compounds, e.g., with regards to plasma half-life.Since the most active compounds are lipophilic in nature, the project will also aim to improve the physicochemical properties, such as water solubility. Towards this goal, further structural modifications will be explored that were not possible because of time constraints in the previous project.The project aims to contribute to the development of novel analgesics with good GI profiles, low addiction potential and low hepatotoxicity.
DFG Programme
Research Grants
