Modifications of the Triaminoaryl Metabophore of Flupirtine and Retigabine Aimed at Avoiding Quinone Diimine Formation.

Andreas Link,Patrick J Bednarski,Anja Bodtke,Konrad W Wurm,Frieda-Marie Bartz,Lukas Schulig

doi:10.1021/acsomega.1c07103

Abstract

The potassium channel opening drugs flupirtine and retigabine have been withdrawn from the market due to occasional drug-induced liver injury (DILI) and tissue discoloration, respectively. While the mechanism underlying DILI after prolonged flupirtine use is not entirely understood, evidence indicates that both drugs are metabolized in an initial step to reactive ortho- and/or para-azaquinone diimines or ortho- and/or para-quinone diimines, respectively. Aiming to develop safer alternatives for the treatment of pain and epilepsy, we have attempted to separate activity from toxicity by employing a drug design strategy of avoiding the detrimental oxidation of the central aromatic ring by shifting oxidation toward the formation of benign metabolites. In the present investigation, an alternative retrometabolic design strategy was followed. The nitrogen atom, which could be involved in the formation of both ortho- or para-quinone diimines of the lead structures, was shifted away from the central ring, yielding a substitution pattern with nitrogen substituents in the meta position only. Evaluation of KV7.2/3 opening activity of the 11 new specially designed derivatives revealed surprisingly steep structure–activity relationship data with inactive compounds and an activity cliff that led to the identification of an apparent “magic methyl” effect in the case of N-(4-fluorobenzyl)-6-[(4-fluorobenzyl)amino]-2-methoxy-4-methylnicotinamide. This flupirtine analogue showed potent KV7.2/3 opening activity, being six times as active as flupirtine itself, and by design is devoid of the potential for azaquinone diimine formation.

Highlights

Reactive drug metabolites are well-known causes of druginduced liver injury (DILI) and other adverse drug reactions and are an important determinant of drug toxicity and failure.1,2 Of 68 drugs that were retroactively recalled due to idiosyncratic toxicity or addressed in boxed warnings by theFood and Drug Administration, an association with the formation of reactive metabolites was found in 62−69% of the cases.3 Two current examples that reflect this problem are the KV7 channel openers flupirtine [1] and retigabine (2, USAN: ezogabine)
It is able to predict atom pairs that form quinones with an area under the curve (AUC) accuracy of 97.6% and identify molecules that form quinones with 88.2% AUC.30
A visualization of the results of compound 36b as a representative example for this substance class is contained in Table 1, which underlines that in contrast to flupirtine and retigabine, no risk for the formation of quinoid metabolites is to be feared for the inverted amide scaffold

Summary

Introduction

Reactive drug metabolites are well-known causes of druginduced liver injury (DILI) and other adverse drug reactions and are an important determinant of drug toxicity and failure. Of 68 drugs that were retroactively recalled due to idiosyncratic toxicity or addressed in boxed warnings by theFood and Drug Administration, an association with the formation of reactive metabolites was found in 62−69% of the cases. Two current examples that reflect this problem are the KV7 channel openers flupirtine [1] and retigabine (2, USAN: ezogabine). An in vitro assay showed the formation of glutathione conjugates after enzymatic oxidation by peroxidases, and in a clinical study, mercapturic acid derivatives were detected in the urine of healthy human subjects treated with flupirtine, both of which are indicators for the formation of reactive azaquinone diimine metabolites [5]. The rarity of the hepatotoxic reactions under flupirtine treatment as well as the lack of a clear dose dependency rather suggests the hapten hypothesis and the involvement of the adaptive immune system. This assumption is backed by histological findings and the identification of a certain human leukocyte antigen gene as a genetic risk factor for flupirtine-induced hepatotoxicity.. This assumption is backed by histological findings and the identification of a certain human leukocyte antigen gene as a genetic risk factor for flupirtine-induced hepatotoxicity. The hypothesis that pharmacogenetic causes, such as polymorphisms of metabolizing enzymes, contribute to flupirtineinduced hepatotoxicity could not be confirmed in a clinical study.

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Conclusion