C-11, a New Antiepileptic Drug Candidate: Evaluation of the Physicochemical Properties and Impact on the Protective Action of Selected Antiepileptic Drugs in the Mouse Maximal Electroshock-Induced Seizure Model

Zagaja, Mirosław; Szewczyk, Aleksandra; Szala-Rycaj, Joanna; Raszewski, Grzegorz; Chrościńska–Krawczyk, Magdalena; Abram, Michał; Kamiński, Krzysztof; Andres-Mach, Marta

doi:10.3390/molecules26113144

Cited by 6 publications

(11 citation statements)

References 59 publications

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“…compounds at various pretreatment times (i.e., 15, 30, 60, 120 min) ranged from 1.7 to even 6.2 ( Table 3 ). Taking into account the fact that, according to the literature data, compounds with a protective index value above 5, and sometimes even 2, should be taken for further research, and if we take into account the PI values obtained by valproate, the most commonly used in pharmacotherapy of epilepsy, then it can be concluded that the compounds constitute a group of good candidates for further research [ 30 , 31 ]. The anticonvulsant effect of 3 and 4 , expressed as ED 50 values at their peaks of anticonvulsant activity, was also higher than that of valproate—the most commonly used AED ( p < 0.0001, Table S3 ).…”

Section: Resultsmentioning

confidence: 99%

Effect of Linker Elongation on the VGSC Affinity and Anticonvulsant Activity among 4-Alkyl-5-aryl-1,2,4-triazole-3-thione Derivatives

et al. 2023

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The main aim of the current project was to investigate the effect of the linker size in 4-alkyl-5-aryl-1,2,4-triazole-3-thione derivatives, known as a group of antiepileptic drug candidates, on their affinity towards voltage-gated sodium channels (VGSCs). The rationale of the study was based both on the SAR observations and docking simulations of the interactions between the designed ligands and the binding site of human VGSC. HYDE docking scores, which describe hydrogen bonding, desolvation, and hydrophobic effects, obtained for 5-[(3-chlorophenyl)ethyl]-4-butyl/hexyl-1,2,4-triazole-3-thiones, justified their beneficial sodium channel blocking activity. The results of docking simulations were verified using a radioligand binding assay with [3H]batrachotoxin. Unexpectedly, although the investigated triazole-based compounds acted as VGSC ligands, their affinities were lower than those of the respective analogs containing shorter alkyl linkers. Since numerous sodium channel blockers are recognized as antiepileptic agents, the obtained 1,2,4-triazole derivatives were examined for antiepileptic potential using an experimental model of tonic–clonic seizures in mice. Median effective doses (ED50) of the compounds examined in MES test reached 96.6 ± 14.8 mg/kg, while their median toxic doses (TD50), obtained in the rotarod test, were even as high as 710.5 ± 47.4 mg/kg.

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Section: Resultsmentioning

confidence: 99%

Effect of Linker Elongation on the VGSC Affinity and Anticonvulsant Activity among 4-Alkyl-5-aryl-1,2,4-triazole-3-thione Derivatives

et al. 2023

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“…Furthermore, KA-11 significantly stimulated the proliferation migration and differentiation of newborn cells into neurons and astrocytes, as well as protected the cognitive functions in the mouse PILO-induced status epilepticus (PILO-induced SE) [11]. Finally, our last studies using KA-11 in combination with several selected ASDs in the mouse model of an MES test indicated a significant pharmacodynamic impact of KA-11 on the antiseizure action of two ASDs, lacosamide and valproate, with no adverse effects among the tested drugs [8]. Moreover, in silico studies indicated that KA-11 meets the drug-likeness criteria resulting from Lipinski's [12] and Veber's [13] rules, as well as the prediction of gastrointestinal absorption and brain penetration (according to Instant JChem by the ChemAxon software version 21.4.0).…”

Section: Introductionmentioning

confidence: 82%

“…Over the past several years, we have been conducting intensive research on a new hybrid compound, a 2-(2,5-dioxopyrrolidin-1-yl)propanamide derivative, compound KA-11 (also named C-11), which, as a hybrid molecule, combines structural fragments of three ASDs: ethosuximide, levetiracetam and 2 of 23 lacosamide. The results of our previous in vitro studies and animal models of epilepsy clearly showed that the hybrid KA-11 has strong antiseizure and neuroprotective properties in acute mouse seizure models: maximal electroshock seizures (MES), subcutaneous pentylenetetrazole (scPTZ) seizures, pilocarpine (PILO) seizures and the 6 Hz seizure model [6,8]. Moreover, we have shown that KA-11 suppresses seizures after repeated administration of PTZ in the mouse kindling model of epilepsy [9].…”

Section: Introductionmentioning

confidence: 89%

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In Vivo and In Vitro Characterization of Close Analogs of Compound KA-11, a New Antiseizure Drug Candidate

Andres-Mach

Zagaja

Szala-Rycaj

et al. 2023

IJMS

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Epilepsy is a neurological disorder involving a number of disease syndromes with a complex etiology. A properly matched antiseizure drug (ASD) gives remission in up to 70% of patients. Nevertheless, there is still a group of about 30% of patients suffering from drug-resistant epilepsy. Consequently, the development of new more effective and/or safer ASDs is still an unmet clinical need. Thus, our current studies were focused on the structural optimization/modifications of one of the leading compounds, KA-11, aiming at the improvement of its antiseizure activity. As a result, we designed and synthesized two close analogs with highly pronounced drug-like physicochemical properties according to in silico predictions, namely KA-228 and KA-232, which were subsequently tested in a panel of animal seizure models, i.e., MES, 6 Hz (32 mA), scPTZ and ivPTZ. Among these compounds, KA-232, which was designed as a water-soluble salt, was distinctly more effective than KA-228 and assured similar antiseizure protection as its chemical prototype KA-11. With the aim of a more detailed characterization of both new molecules, in vitro binding tests were performed to evaluate the potential mechanisms of action. Furthermore, KA-232 was also evaluated in several ADME-Tox studies, and the results obtained strongly supported its drug-like potential. The proposed chemical modification of KA-11 enabled the identification of new pharmacologically active chemotypes, particularly water-soluble KA-232, which, despite the lack of better efficacy than the leading compound, may be used as a chemical prototype for the development of new ASDs, as well as substances potentially active in other neurological or neurodegenerative conditions.

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“…Similar to AS-1, the same research team developed a series of multifunctional ASMs with hybrid structures integrating fragments of ethosuximide, levetiracetam, and lacosamide [69][70][71]. C-11 (former name KA-11) is recognized as a new hybrid compound derived from 2-(2,5-dioxopyrrolidin-1-yl) propanamide [72]. As shown in previous quantitative studies, C-11 demonstrated promising, broad-spectrum antiseizure activities in several preclinical animal models including MES, s.c. PTZ, and 6 Hz (32 mA) psychomotor seizure models [73].…”

Section: -(25-dioxopyrrolidin-1-yl) Propanamide Derivative (C-11)mentioning

confidence: 99%

Identification of New Antiseizure Medication Candidates in Preclinical Animal Studies

Yang,

Wu,

Lai

et al. 2023

IJMS

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Epilepsy is a multifactorial neurologic disease that often leads to many devastating disabilities and an enormous burden on the healthcare system. Until now, drug-resistant epilepsy has presented a major challenge for approximately 30% of the epileptic population. The present article summarizes the validated rodent models of seizures employed in pharmacological researches and comprehensively reviews updated advances of novel antiseizure candidates in the preclinical phase. Newly discovered compounds that demonstrate antiseizure efficacy in preclinical trials will be discussed in the review. It is inspiring that several candidates exert promising antiseizure activities in drug-resistant seizure models. The representative compounds consist of derivatives of hybrid compounds that integrate multiple approved antiseizure medications, novel positive allosteric modulators targeting subtype-selective γ-Aminobutyric acid type A receptors, and a derivative of cinnamamide. Although the precise molecular mechanism, pharmacokinetic properties, and safety are not yet fully clear in every novel antiseizure candidate, the adapted approaches to design novel antiseizure medications provide new insights to overcome drug-resistant epilepsy.

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C-11, a New Antiepileptic Drug Candidate: Evaluation of the Physicochemical Properties and Impact on the Protective Action of Selected Antiepileptic Drugs in the Mouse Maximal Electroshock-Induced Seizure Model

Cited by 6 publications

References 59 publications

Effect of Linker Elongation on the VGSC Affinity and Anticonvulsant Activity among 4-Alkyl-5-aryl-1,2,4-triazole-3-thione Derivatives

Effect of Linker Elongation on the VGSC Affinity and Anticonvulsant Activity among 4-Alkyl-5-aryl-1,2,4-triazole-3-thione Derivatives

In Vivo and In Vitro Characterization of Close Analogs of Compound KA-11, a New Antiseizure Drug Candidate

Identification of New Antiseizure Medication Candidates in Preclinical Animal Studies

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