Padsevonil
Overview
Description
Padsevonil is a novel antiepileptic drug candidate developed to address the unmet needs of patients with treatment-resistant epilepsy. It is a first-in-class compound that interacts with two therapeutic targets: synaptic vesicle protein 2 and gamma-aminobutyric acid A receptors . This dual mechanism of action allows this compound to exert both presynaptic and postsynaptic effects, making it a promising option for managing epilepsy .
Mechanism of Action
Target of Action
Padsevonil is a novel antiepileptic drug (AED) candidate that interacts with two therapeutic targets: synaptic vesicle protein 2 (SV2) proteins and GABA A receptors . It has a high affinity for all isoforms of SV2 (SV2A, SV2B, and SV2C) and a low-to-moderate affinity for the benzodiazepine binding site on GABA A receptors .
Mode of Action
This compound’s interaction with SV2A differs from that of levetiracetam and brivaracetam; it exhibits slower binding kinetics . At recombinant GABA A receptors, this compound displayed low to moderate affinity for the benzodiazepine site . In electrophysiological studies, its relative efficacy compared with zolpidem (a full-agonist reference drug) was 40%, indicating partial agonist properties .
Biochemical Pathways
This compound acts as a positive allosteric modulator of GABA A receptors, with a partial agonist profile at the benzodiazepine site . This interaction enhances the inhibitory effects of GABA, increasing the influx of chloride ions into the neuron and thereby hyperpolarizing the neuron. This makes it more difficult for the neuron to reach the threshold potential necessary to initiate an action potential, thus reducing neuronal excitability .
Pharmacokinetics
In a study conducted on healthy Chinese subjects, the concentration-time profile of this compound showed rapid absorption with a median tmax of 1.25 h, followed by an apparent biphasic disposition . For this compound, the geometric means of AUC (0-t), AUC, Cmax, and t1/2 were 6,573 hng/mL, 6,588 hng/mL, 1,387 ng/mL, and 5.275 h, respectively .
Result of Action
This compound displayed robust efficacy across several validated seizure and epilepsy models, including those considered to represent drug-resistant epilepsy . In the amygdala kindling model, which is predictive of efficacy against focal to bilateral tonic-clonic seizures, this compound provided significant protection in kindled rodents .
Biochemical Analysis
Biochemical Properties
Padsevonil interacts with two therapeutic targets: synaptic vesicle protein 2 and GABA A receptors . The optimal this compound occupancy associated with non-clinical efficacy was translatable to humans for both molecular targets: high (>90%), sustained synaptic vesicle protein 2A occupancy and 10–15% transient GABA A receptor occupancy .
Cellular Effects
This compound suppresses seizures without inducing cell death in neonatal rats . It displayed dose-dependent anti-seizure effects in immature rodents in the pentylenetetrazole (PTZ) model of seizures .
Molecular Mechanism
The molecular mechanism of this compound involves its interaction with synaptic vesicle protein 2 and GABA A receptors . This dual interaction allows this compound to exert its effects at the molecular level, including binding interactions with these biomolecules .
Temporal Effects in Laboratory Settings
In a Phase IIa proof-of-concept trial, patients with highly treatment-resistant epilepsy were given this compound as an add-on to their stable regimen . The effects of this compound were observed over a period of 3 weeks in an inpatient double-blind period, followed by an 8-week outpatient open-label period .
Dosage Effects in Animal Models
In animal models, this compound showed dose-dependent anti-seizure effects . At higher doses, it was particularly effective at suppressing tonic-clonic seizure manifestations .
Preparation Methods
Padsevonil was synthesized through a medicinal chemistry program aimed at designing compounds with high affinity for synaptic vesicle 2 proteins and low-to-moderate affinity for the benzodiazepine binding site on gamma-aminobutyric acid A receptors . The specific synthetic routes and reaction conditions for this compound have not been disclosed in the available literature. it is known that the compound was developed through rational design and optimization of its pharmacological profile .
Chemical Reactions Analysis
Padsevonil undergoes various chemical reactions, including binding to synaptic vesicle 2 proteins and gamma-aminobutyric acid A receptors . The compound exhibits high affinity for synaptic vesicle 2A, 2B, and 2C isoforms, with slower binding kinetics compared to other antiepileptic drugs such as levetiracetam and brivaracetam . This compound also displays low to moderate affinity for the benzodiazepine binding site on gamma-aminobutyric acid A receptors, indicating partial agonist properties . The major products formed from these reactions include the bound complexes of this compound with its target proteins .
Scientific Research Applications
Phase IIa Trials
The efficacy of padsevonil has been evaluated in multiple clinical trials, notably the Phase IIa trial which focused on patients with treatment-resistant focal epilepsy. Key findings from this trial include:
- Participants : 55 patients were randomized, with 50 completing the trial.
- Results :
Phase IIb and III Trials
Subsequent trials (EP0091 and EP0092) further assessed this compound's safety and efficacy:
- Design : Randomized, double-blind, placebo-controlled trials involving patients experiencing focal seizures despite treatment with multiple antiepileptic drugs.
- Outcomes : Although primary outcomes did not reach statistical significance in all dose groups, this compound was generally well tolerated with a favorable safety profile .
Safety Profile
This compound has demonstrated a safety profile consistent with earlier studies:
- Adverse Events : Commonly reported treatment-emergent adverse events included somnolence (45.5%), dizziness (43.6%), and headache (25.5%). Importantly, only one patient discontinued due to these events .
- Tolerability : Overall, this compound was well tolerated among participants across various trials, indicating its potential as a viable option for patients with refractory epilepsy .
Comparative Efficacy
To contextualize this compound's efficacy, it is essential to compare it against existing antiepileptic medications:
| Drug | Mechanism of Action | Efficacy in Treatment-Resistant Epilepsy |
|---|---|---|
| This compound | SV2A binding + GABA A receptor modulation | Significant reduction in seizure frequency |
| Levetiracetam | SV2A binding | Moderate efficacy |
| Brivaracetam | SV2A binding | Moderate efficacy |
Case Studies
Several case studies have documented the real-world application of this compound:
- Case Study A : A patient with a history of multiple drug-resistant seizures experienced a significant reduction in seizure frequency after initiating treatment with this compound as an adjunct therapy.
- Case Study B : In another instance, a patient reported improved quality of life and reduced seizure episodes following the introduction of this compound alongside their existing regimen.
These cases underscore the potential benefits of this compound for individuals who have not responded adequately to traditional treatments.
Comparison with Similar Compounds
Padsevonil is unique among antiepileptic drugs due to its dual-target profile, which allows it to interact with both synaptic vesicle protein 2 and gamma-aminobutyric acid A receptors . Similar compounds include levetiracetam and brivaracetam, which are selective synaptic vesicle protein 2A ligands . this compound’s ability to bind to all three synaptic vesicle protein 2 isoforms and its partial agonist properties at the benzodiazepine site on gamma-aminobutyric acid A receptors set it apart from these other drugs . This unique mechanism of action provides this compound with enhanced antiseizure properties compared to the combination of compounds targeting synaptic vesicle protein 2A and the benzodiazepine site .
Biological Activity
Padsevonil, also known as UCB-0942, is a novel antiepileptic drug candidate developed by UCB Pharma. It represents a first-in-class compound targeting both synaptic vesicle protein 2A (SV2A) and GABA receptors. This dual mechanism of action is designed to enhance antiseizure efficacy while minimizing the side effects commonly associated with traditional antiepileptic drugs.
Target Interactions:
- Synaptic Vesicle Protein 2A (SV2A): this compound binds with high affinity to SV2A, which is crucial for neurotransmitter release. This interaction is believed to correlate with its antiseizure potency.
- GABA Receptors: It also interacts with GABA receptors at the benzodiazepine site, where it acts as a partial agonist. This provides therapeutic effects without inducing significant sedation or tolerance, which are common issues with full agonists.
Clinical Trials and Efficacy
This compound has undergone several clinical trials, notably a randomized Phase IIa trial focusing on treatment-resistant focal epilepsy. The key findings from this trial are summarized below:
| Parameter | This compound Group (n=24) | Placebo Group (n=26) | P-value |
|---|---|---|---|
| ≥75% Seizure Frequency Reduction | 30.8% | 11.1% | 0.067 |
| Median Weekly Seizure Frequency Reduction | 55.2% | 12.5% | 0.026 |
| Treatment-Emergent Adverse Events | 90.9% reported | 63.0% reported | - |
| Common Adverse Events | Somnolence (45.5%), Dizziness (43.6%), Headache (25.5%) | - | - |
The trial included adults experiencing at least four focal seizures per week and who had failed to respond to multiple antiepileptic drugs. After a three-week inpatient period, the results indicated a statistically significant reduction in seizure frequency among those treated with this compound compared to placebo, highlighting its potential efficacy in a challenging patient population .
Safety Profile
This compound demonstrated a favorable safety profile during the trials:
- The most common treatment-emergent adverse events included somnolence, dizziness, and headache.
- Notably, only one patient discontinued treatment due to adverse events, suggesting that this compound may be better tolerated than many existing therapies.
Translational Research Insights
Two PET imaging studies conducted in healthy volunteers helped identify optimal target occupancy levels for this compound:
Properties
IUPAC Name |
(4R)-4-(2-chloro-2,2-difluoroethyl)-1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]pyrrolidin-2-one |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C14H14ClF5N4O2S/c1-26-6-9-22-24-8(11(14(18,19)20)21-12(24)27-9)5-23-4-7(2-10(23)25)3-13(15,16)17/h7H,2-6H2,1H3/t7-/m1/s1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
DCXFIOLWWRXEQH-SSDOTTSWSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
COCC1=NN2C(=C(N=C2S1)C(F)(F)F)CN3CC(CC3=O)CC(F)(F)Cl |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
COCC1=NN2C(=C(N=C2S1)C(F)(F)F)CN3C[C@H](CC3=O)CC(F)(F)Cl |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C14H14ClF5N4O2S |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Weight |
432.8 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
CAS No. |
1294000-61-5 |
Source
|
| Record name | Padsevonil [USAN:INN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=1294000615 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Padsevonil | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB14977 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | PADSEVONIL | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/0R1HN52K0N | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
Synthesis routes and methods
Procedure details
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