How to Replace the Lost keys? Strategies Toward Safer K _V 7 Channel Openers

Abstract

The highly structurally similar drugs flupirtine and retigabine have been regarded as safe and effective for many years but lately they turned out to exert intolerable side effects. While the twin molecules share the mode of action, both stabilize the open state of voltage-gated potassium channels, the form and severity of adverse effects is different. The analgesic flupirtine caused drug-induced liver injury in rare but fatal cases, whereas prolonged use of the antiepileptic retigabine led to blue tissue discoloration. Because the adverse effects seem unrelated to the mode of action, it is likely, that both drugs that occupied important therapeutic niches, could be replaced. Reasons for the clinically relevant toxicity will be clarified and future substitutes for these drugs presented in this review.

Sulfide Analogues of Flupirtine and Retigabine with Nanomolar KV7.2/KV7.3 Channel Opening Activity

“…The mechanism underlying DILI after prolonged flupirtine use is not entirely understood, but evidence indicates that the drug might be metabolized to reactive intermediates ( 3 and its ortho ‐azaquinone diimine isomer), that react with endogenous nucleophiles . Specifically, the detection of cysteine conjugates in the urine of healthy subjects after oral administration of 1 strongly indicates the formation of reactive intermediates of flupirtine .…”

The ups and downs of alkyl‐carbamates in epilepsy therapy: How does cenobamate differ?

“…For experienced pharmacologists and toxicologists, these idiosyncratic adverse events of felbamate were not entirely surprising, because induction of aplastic anemia was previously reported for the structurally similar alkyl‐dicarbamate meprobamate 11,12 . In a later development, a new type of adverse effect (i.e., blue skin discoloration and pigment changes in the retina) was reported for retigabine, leading to its withdrawal in 2017 13 …”

“…Flupirtine is another example of an alkyl‐carbamate that induces rare but potentially fatal idiosyncratic liver toxicity, a characteristic it does not seemingly share with the structurally similar drug retigabine 13 . Even after more than 30 years of use, the hepatotoxicity of flupirtine is still poorly understood.…”

“…The FDA subsequently recommended eye examinations every 6 months and discontinuation of the drug when eye discolorations were observed. The incidence rate of tissue discoloration is reported to be 3.6% per patient‐year, with a median onset of approximately 4 years 13 . In biopsy samples of discolored tissue, dimers of retigabine and dimers of its main metabolite were found, partly in conjunction with melanin 13 .…”

“…The incidence rate of tissue discoloration is reported to be 3.6% per patient‐year, with a median onset of approximately 4 years 13 . In biopsy samples of discolored tissue, dimers of retigabine and dimers of its main metabolite were found, partly in conjunction with melanin 13 . These dimers might be responsible for the abnormal pigmentation under retigabine treatment, which is considered an idiosyncratic adverse event.…”