27048-04-0Relevant articles and documents
Flupirtine Analogues: Explorative Synthesis and Influence of Chemical Structure on KV7.2/KV7.3 Channel Opening Activity
Surur, Abdrrahman S.,Beirow, Kristin,Bock, Christian,Schulig, Lukas,Kindermann, Markus K.,Bodtke, Anja,Siegmund, Werner,Bednarski, Patrick J.,Link, Andreas
, p. 41 - 44 (2019)
Neuronal voltage-gated potassium channels KV7.2/KV7.3 are sensitive to small-molecule drugs such as flupirtine, even though physiological response occurs in the absence of ligands. Clinically, prolonged use of flupirtine as a pain medication is associated with rare cases of drug-induced liver injury. Thus, safety concerns prevent a broader use of this non-opioid and non-steroidal analgesic in therapeutic areas with unmet medical needs such as hyperactive bladder or neonatal seizures. With the goal of studying influences of chemical structure on activity and toxicity of flupirtine, we explored modifications of the benzylamino bridge and the substitution pattern in both rings of flupirtine. Among twelve derivatives, four novel thioether derivatives showed the desired activity in cellular assays and may serve as leads for safer KV channel openers.
Pyrido[2,3-b]pyrazine-3(4H)-ketone derivative and application thereof
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Paragraph 0015-0016; 0033, (2021/03/13)
The invention provides a pyrido[2,3-b]pyrazine-3(4H)-ketone derivative and application thereof. The structural general formula of the pyrido[2,3-b]pyrazine-3(4H)-ketone derivative is a formula V, andthe pyrido[2,3-b]pyrazine-3(4H)-ketone derivative comprises pharmaceutically acceptable salt, solvate, hydrate or crystal form thereof. The compound provided by the invention is an active ligand of afibroblast growth factor receptor (FGFR), and research shows that the compound shown in the structure V has good anti-proliferative activity on KATO III gastric cancer cells (FGFR2 amplification) andHuh-7 liver cancer cells (FGFR4 overexpression), and is applied to preparation of drugs for treating tumor-related diseases caused by FGFR abnormal activation as an FGFR inhibitor. The structural general formula V is shown in the description.
Sulfide Analogues of Flupirtine and Retigabine with Nanomolar KV7.2/KV7.3 Channel Opening Activity
Bock, Christian,Surur, Abdrrahman S.,Beirow, Kristin,Kindermann, Markus K.,Schulig, Lukas,Bodtke, Anja,Bednarski, Patrick J.,Link, Andreas
supporting information, p. 952 - 964 (2019/04/10)
The potassium channel openers flupirtine and retigabine have proven to be valuable analgesics or antiepileptics. Their recent withdrawal due to occasional hepatotoxicity and tissue discoloration, respectively, leaves a therapeutic niche unfilled. Metabolic oxidation of both drugs gives rise to the formation of electrophilic quinones. These elusive, highly reactive metabolites may induce liver injury in the case of flupirtine and blue tissue discoloration after prolonged intake of retigabine. We examined which structural features can be altered to avoid the detrimental oxidation of the aromatic ring and shift oxidation toward the formation of more benign metabolites. Structure–activity relationship studies were performed to evaluate the KV7.2/3 channel opening activity of 45 derivatives. Sulfide analogues were identified that are devoid of the risk of quinone formation, but possess potent KV7.2/3 opening activity. For example, flupirtine analogue 3-(3,5-difluorophenyl)-N-(6-(isobutylthio)-2-(pyrrolidin-1-yl)pyridin-3-yl)propanamide (48) has 100-fold enhanced activity (EC50=1.4 nm), a vastly improved toxicity/activity ratio, and the same efficacy as retigabine in vitro.
