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| Targets |
Synaptic vesicle protein 2 (SV2A, SV2B, SV2C) and GABA A receptors. Padsevonil is a first-in-class investigational small molecule that uniquely combines high-affinity binding to all three SV2 isoforms (SV2A, SV2B, SV2C) with GABA A receptor modulation. SV2A is the target of the antiepileptic drug levetiracetam, and its modulation is thought to reduce neurotransmitter release and synaptic excitability. GABA A receptors are the primary inhibitory neurotransmitter receptors in the brain, and their positive modulation enhances inhibitory neurotransmission, reducing neuronal excitability. By combining these two mechanisms, Padsevonil offers a novel approach to epilepsy treatment that may provide enhanced efficacy and a broader spectrum of activity compared to existing antiepileptic drugs. The compound also functions as a pre- and post-synaptic inhibitor, further reducing synaptic excitability. Padsevonil is being developed for the treatment of drug-refractory epilepsy and partial-onset seizures.
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| ln Vitro |
Padsevonil is a first-in-class antiepileptic agent that uniquely combines high-affinity binding to all three SV2 isoforms (SV2A, SV2B, SV2C) with GABA A receptor modulation. The compound's dual mechanism of action distinguishes it from other antiepileptic drugs and may provide enhanced efficacy and a broader spectrum of activity. By binding to SV2 proteins, Padsevonil reduces neurotransmitter release and synaptic excitability. By modulating GABA A receptors, the compound enhances inhibitory neurotransmission. Padsevonil also functions as a pre- and post-synaptic inhibitor, further reducing synaptic excitability. The compound has been evaluated in preclinical studies for its antiepileptic activity and has shown promising results. Padsevonil has completed Phase 2 clinical trials for epilepsy.
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| ln Vivo |
Padsevonil has been evaluated in vivo in animal models of epilepsy and in clinical trials. The compound is an orally administered small molecule that has shown antiepileptic activity in preclinical models. Padsevonil uniquely combines high-affinity binding to all three SV2 isoforms with GABA A receptor modulation, providing a novel mechanism of action for epilepsy treatment. The compound has completed Phase 2 clinical trials for drug-refractory epilepsy and partial-onset seizures. Clinical studies have assessed the compound's safety, tolerability, pharmacokinetics, and efficacy in patients with epilepsy. Detailed clinical trial data are available from published studies. Padsevonil is for research use only and is not for human therapeutic use.
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| Enzyme Assay |
SV2 binding assays are performed using membranes prepared from cells expressing recombinant SV2A, SV2B, or SV2C. Radioligand binding studies use [³H]-levetiracetam or other SV2 ligands. Membrane preparations are incubated with varying concentrations of Padsevonil and a fixed concentration of radioligand in binding buffer for 60-120 minutes at room temperature. Non-specific binding is determined using excess unlabeled levetiracetam. Bound radioactivity is measured by scintillation counting after filtration through GF/B filters. IC50 and Ki values are calculated by non-linear regression. GABA A receptor modulation is assessed by measuring GABA-induced chloride currents in cells expressing recombinant GABA A receptors using patch-clamp electrophysiology or by measuring GABA-mediated effects in brain slices.
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| Cell Assay |
Cellular SV2 binding and GABA A receptor modulation are evaluated in cell lines expressing recombinant SV2 proteins or GABA A receptors. Cells are cultured in appropriate media at 37°C with 5% CO₂ and treated with Padsevonil at various concentrations. SV2 binding is assessed using radioligand binding assays. GABA A receptor modulation is assessed by measuring GABA-induced chloride influx using fluorescent chloride indicators (e.g., MQAE) or by patch-clamp electrophysiology. Cell viability is assessed using MTT or LDH assays. Each experiment includes vehicle controls (DMSO) and appropriate positive controls (e.g., levetiracetam for SV2 binding, diazepam for GABA A modulation).
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| Animal Protocol |
In vivo efficacy of Padsevonil is evaluated in animal models of epilepsy, such as the maximal electroshock seizure test, pentylenetetrazole-induced seizure model, and kindling models. The compound is administered orally or intraperitoneally at doses determined by preclinical studies. Seizure activity is monitored by behavioral observation and EEG recordings. The compound's ability to prevent or reduce seizure activity is assessed. Pharmacokinetic parameters are assessed in parallel. Clinical trials have been conducted for drug-refractory epilepsy and partial-onset seizures. In Phase 2 trials, the compound's efficacy, safety, and tolerability were evaluated in patients with epilepsy. Sample sizes in clinical trials typically range from 50-200 patients per group.
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| ADME/Pharmacokinetics |
Molecular Weight: 432.8. Formula: C14H14ClF5N4O2S. CAS No.: 1294000-61-5. Synonyms: Padsevonil; UCB-0942; UCB0942. Appearance: Solid. Purity: Typically ≥98%. Solubility: Soluble in DMSO. Storage: Typically at -20°C. Padsevonil is a first-in-class antiepileptic agent that uniquely combines high-affinity binding to all three SV2 isoforms with GABA A receptor modulation.
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| Toxicity/Toxicokinetics |
Padsevonil has been evaluated in clinical trials for safety and efficacy. The compound is generally well-tolerated at therapeutic doses. Common adverse effects may include dizziness, somnolence, headache, and fatigue. As a CNS-active compound, Padsevonil may also cause cognitive impairment and other neurological effects. Standard toxicology studies have been conducted as part of the clinical development program. The compound has completed Phase 2 clinical trials for drug-refractory epilepsy and partial-onset seizures. Regulatory approvals have not been reported.
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| References |
: Zaccara G, Schmidt D. Do traditional anti-seizure drugs have a futureA review of potential anti-seizure drugs in clinical development. Pharmacol Res. 2016 Feb;104:38-48. doi: 10.1016/j.phrs.2015.12.011. Epub 2015 Dec 12. Review. PubMed PMID: 26689774.
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| Additional Infomation |
Padsevonil is being studied in the clinical trial NCT03695094 (a study in patients with epilepsy aimed at evaluating the pharmacokinetics, safety, and tolerability of oxcarbazepine in response to Padsevonil).
Padsevonil is also known as UCB-0942 and UCB0942. Its IUPAC name is (R)-4-(2-chloro-2,2-difluoroethyl)-... (full name not fully resolved). Padsevonil is a first-in-class, orally administered small molecule being developed by UCB Biopharma for the treatment of drug-refractory epilepsy and partial-onset seizures. Padsevonil uniquely combines high-affinity binding to all three SV2 isoforms (SV2A, SV2B, SV2C) with GABA A receptor modulation, providing a novel approach to epilepsy treatment. The compound has completed Phase 2 clinical trials for epilepsy. No regulatory approvals have been reported. Padsevonil is for research use only. |
| Molecular Formula |
C14H14CLF5N4O2S
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| Molecular Weight |
432.79657793045
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| Exact Mass |
432.044
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| CAS # |
1294000-61-5
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| PubChem CID |
52911611
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| Appearance |
White to off-white solid powder
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| Density |
1.7±0.1 g/cm3
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| Index of Refraction |
1.608
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| LogP |
1.63
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
27
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| Complexity |
572
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| Defined Atom Stereocenter Count |
1
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| SMILES |
ClC(C[C@H]1CC(N(CC2=C(C(F)(F)F)N=C3N2N=C(COC)S3)C1)=O)(F)F
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| InChi Key |
DCXFIOLWWRXEQH-SSDOTTSWSA-N
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| InChi Code |
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
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| Chemical Name |
(R)-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
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| Synonyms |
UCB-0942 UCB 0942 UCB0942
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~231.05 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.78 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.78 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3105 mL | 11.5527 mL | 23.1054 mL | |
| 5 mM | 0.4621 mL | 2.3105 mL | 4.6211 mL | |
| 10 mM | 0.2311 mL | 1.1553 mL | 2.3105 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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