Seletracetam
Identification
- Generic Name
- Seletracetam
- DrugBank Accession Number
- DB05885
- Background
Seletracetam is a pyrrolidone derivative and with a structural similarity to newer generation antiepileptic drug levetiracetam. It binds to the same target as levetiracetam but with higher affinity and has shown potent seizure suppression in models of acquired and genetic epilepsy with high CNS tolerability. It is predicted to have low drug-drug interactions and inhibition or induction of any major human metabolizing enzymes. Seletracetam was in Phase II clinical trials under the supervision of the U.S. Food and Drug Administration (FDA) investigated as treatment of epilepsy and partial epilepsy however its development had been put on hold in July 2007. As of 2010, its production was further halted due to the investigation of a newer antiepileptic agent, brivaracetam.
- Type
- Small Molecule
- Groups
- Investigational
- Structure
- Weight
- Average: 232.2272
Monoisotopic: 232.102334112 - Chemical Formula
- C10H14F2N2O2
- Synonyms
- (2S)-2-((4S)-4-(2,2-Difluoroethenyl)-2-oxopyrrolidin-1-yl)butanamide
- Seletracetam
- External IDs
- UCB 44212
- UCB-44212
Pharmacology
- Indication
Investigated for use/treatment in epilepsy.
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- Pharmacodynamics
Seletracetam is an antiepileptic agent that targets the presynaptic mechanisms of epilepsy. It interferes with synaptic vesicle exocytosis and neurotransmitter release by binding to synaptic vesicle protein 2A (SV2A) which is involved in synaptic vesicle docking and fusion. It is also a N-type calcium channel blocker that inhibits the abnormal neuronal discharge by inhibiting the calcium channel function and associated calcium currents. Seletracetam markedly reduces epileptiform markers of both hyper-excitability and hyper-synchronization in an in vitro slice model of epilepsy and potently suppresses seizures in in vivo epilepsy models mimicking both partial and generalized epilepsy 7.
- Mechanism of action
Seletracetam binds to SV2A in a stereospecific and selective manner. SV2A is a membrane glycoprotein present in synaptic vesicles of neurons that plays a role as calcium regulators in neurotransmitter release and modulate synaptic networks. Seletracetam is thought to reduce excessive neuronal activity by modulating SV2A function and restoring the ability of a neuron to regulate its neurotransmitter release. Seizure generation induces a sustained membrane depolarization causing a prolonged firing of voltage-dependent calcium currents sufficient to induce a significant rise in calcium concentration. High voltage-activated calcium currents are inhibited by seletracetam by blocking N-type calcium channels in the pyramidal neurons. The drug reduces the degree of calcium influx and decreases the intraneuronal calcium concentration, blocking the abnormal fluctuations in membrane potential occurring during epileptic discharges.
Target Actions Organism ASynaptic vesicle glycoprotein 2A modulatorHumans AVoltage-dependent N-type calcium channel subunit alpha-1B blockerHumans UGlycine receptor (alpha-1/beta) bindingHumans - Absorption
Seletracetam is rapidly absorbed following oral administration, reaching the Cmax within 1 hour and displaying oral bioavailability of >90%.
- Volume of distribution
The volume of distribution is approximately 0.6 L/kg, which is close to that of total body water.
- Protein binding
Demonstrates low plasma protein binding (<10%)
- Metabolism
It undergoes hydrolysis of the acetamide group to form the carboxylic acid metabolite ucb-101596-1, which is pharmacologically inactive.
- Route of elimination
Primarily eliminated through renal excretion. It is as mainly excreted as unchanged drug (30%) and an acidic metabolite ucb-101596-1 (60%).
- Half-life
Approximately 8 hours in healthy young male subjects.
- Clearance
The total apparent clearance is approximately 0.8mL/min/kg.
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
High doses of 2000 mg/kg/day in the mouse and rat and ≥600 mg/kg/day in the dog were not well tolerated in animal studies. Seletracetam does not possess potential teratogenic, reproductive or embryonic toxicities. Most adverse effects are CNS-related effects, including somnolence, dizziness, feeling drunk, euphoria and nausea which all usually tend to be resolved within 24 hours.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Seletracetam can be increased when it is combined with Abametapir. Acarbose The risk or severity of hypoglycemia can be increased when Seletracetam is combined with Acarbose. Acebutolol Acebutolol may increase the arrhythmogenic activities of Seletracetam. Aceclofenac The risk or severity of hyperkalemia can be increased when Seletracetam is combined with Aceclofenac. Acemetacin The risk or severity of hyperkalemia can be increased when Seletracetam is combined with Acemetacin. - Food Interactions
- Not Available
Categories
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as alpha amino acids and derivatives. These are amino acids in which the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (alpha carbon), or a derivative thereof.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- Alpha amino acids and derivatives
- Alternative Parents
- Pyrrolidine-2-ones / Fatty amides / N-alkylpyrrolidines / Tertiary carboxylic acid amides / Primary carboxylic acid amides / Ketene acetals / Lactams / Vinyl fluorides / Azacyclic compounds / Fluoroalkenes show 6 more
- Substituents
- 2-pyrrolidone / Aliphatic heteromonocyclic compound / Alpha-amino acid or derivatives / Azacycle / Carbonyl group / Carboxamide group / Fatty acyl / Fatty amide / Fluoroalkene / Haloalkene show 19 more
- Molecular Framework
- Aliphatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- RFR2CH3QZK
- CAS number
- 357336-74-4
- InChI Key
- ANWPENAPCIFDSZ-RQJHMYQMSA-N
- InChI
- InChI=1S/C10H14F2N2O2/c1-2-7(10(13)16)14-5-6(3-8(11)12)4-9(14)15/h3,6-7H,2,4-5H2,1H3,(H2,13,16)/t6-,7+/m1/s1
- IUPAC Name
- (2S)-2-[(4S)-4-(2,2-difluoroethenyl)-2-oxopyrrolidin-1-yl]butanamide
- SMILES
- CC[C@H](N1C[C@@H](CC1=O)C=C(F)F)C(N)=O
References
- Synthesis Reference
- Wong MG, Defina JA, Andrews PR: Conformational analysis of clinically active anticonvulsant drugs. Journal of Medical Chemistry 1986 (29): 562-72. [PubMed: 3959032]
- Bruno-Blanch L, Gálvez J, García-Domenech R: Topological virtual screening: a way to find new anticonvulsant drugs from chemical diversity 2003 (13): 2749-54. [PubMed: 12873507]
- Kamiński K, Rzepka S ,Obniska J: Synthesis and anticonvulsant activity of new 1-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]pyrrolidine-2,5-diones. Bioorganic & Medicinal Chemistry Letters 2011; 21 (19): 5800–3. [PubMed: 21875804]
- General References
- Bennett B, Matagne A, Michel P, Leonard M, Cornet M, Meeus MA, Toublanc N: Seletracetam (UCB 44212). Neurotherapeutics. 2007 Jan;4(1):117-22. [Article]
- Bialer M: New antiepileptic drugs that are second generation to existing antiepileptic drugs. Expert Opin Investig Drugs. 2006 Jun;15(6):637-47. [Article]
- Gillard M, Chatelain P, Fuks B: Binding characteristics of levetiracetam to synaptic vesicle protein 2A (SV2A) in human brain and in CHO cells expressing the human recombinant protein. Eur J Pharmacol. 2006 Apr 24;536(1-2):102-8. Epub 2006 Mar 10. [Article]
- Ziolkowski H, Jaroszewski JJ, Ziolkowska N, Jasiecka A: Characteristics of selected second-generation antiepileptic drugs used in dogs. Pol J Vet Sci. 2012;15(3):571-82. [Article]
- de Groot M, Toering ST, Boer K, Spliet WG, Heimans JJ, Aronica E, Reijneveld JC: Expression of synaptic vesicle protein 2A in epilepsy-associated brain tumors and in the peritumoral cortex. Neuro Oncol. 2010 Mar;12(3):265-73. doi: 10.1093/neuonc/nop028. Epub 2010 Jan 6. [Article]
- Luszczki JJ: Third-generation antiepileptic drugs: mechanisms of action, pharmacokinetics and interactions. Pharmacol Rep. 2009 Mar-Apr;61(2):197-216. [Article]
- Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Perucca E, Tomson T: Progress report on new antiepileptic drugs: a summary of the Eigth Eilat Conference (EILAT VIII). Epilepsy Res. 2007 Jan;73(1):1-52. Epub 2006 Dec 8. [Article]
- 59. (2004). In The Treatment of Epilepsy (2nd ed., pp. 736). John Wiley & Sons. [ISBN:0-632-06046-8]
- External Links
- KEGG Drug
- D05817
- PubChem Compound
- 9942725
- PubChem Substance
- 175427051
- ChemSpider
- 8118337
- ChEMBL
- CHEMBL3918017
- ZINC
- ZINC000011726774
- Wikipedia
- Seletracetam
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 3 Withdrawn Not Available Epilepsy 1 3 Withdrawn Treatment Epilepsy 1 2 Completed Not Available Partial Epilepsy 1 2 Completed Treatment Partial Epilepsy 1 2, 3 Withdrawn Treatment Partial Epilepsy 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 1.02 mg/mL ALOGPS logP 0.51 ALOGPS logP 0.091 Chemaxon logS -2.4 ALOGPS pKa (Strongest Acidic) 15.36 Chemaxon pKa (Strongest Basic) -1.2 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 2 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 63.4 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 64.33 m3·mol-1 Chemaxon Polarizability 21.1 Å3 Chemaxon Number of Rings 1 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 1.0 Blood Brain Barrier + 0.9859 Caco-2 permeable - 0.5795 P-glycoprotein substrate Substrate 0.5226 P-glycoprotein inhibitor I Inhibitor 0.5203 P-glycoprotein inhibitor II Non-inhibitor 0.9211 Renal organic cation transporter Non-inhibitor 0.7747 CYP450 2C9 substrate Non-substrate 0.8933 CYP450 2D6 substrate Non-substrate 0.8178 CYP450 3A4 substrate Substrate 0.5193 CYP450 1A2 substrate Non-inhibitor 0.7893 CYP450 2C9 inhibitor Non-inhibitor 0.7033 CYP450 2D6 inhibitor Non-inhibitor 0.9242 CYP450 2C19 inhibitor Non-inhibitor 0.6378 CYP450 3A4 inhibitor Non-inhibitor 0.8864 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8343 Ames test Non AMES toxic 0.6472 Carcinogenicity Non-carcinogens 0.839 Biodegradation Not ready biodegradable 1.0 Rat acute toxicity 2.6055 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9688 hERG inhibition (predictor II) Non-inhibitor 0.7837
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS splash10-000l-9510000000-c1e724ddfda61adf65a7 Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-001i-0390000000-f9db71f3779c150d2cf2 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-01r6-0920000000-23261c69341b9304cbe9 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-00xr-0920000000-ca5ef49847df01d59f1e Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-002f-7900000000-cb94c0ca85164374eb80 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-00dm-9500000000-7361d0833e7675a3a252 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0006-9400000000-5632c87c3e0ba9b62168 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 153.53123 predictedDeepCCS 1.0 (2019) [M+H]+ 155.88924 predictedDeepCCS 1.0 (2019) [M+Na]+ 162.04068 predictedDeepCCS 1.0 (2019)
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Modulator
- General Function
- Transmembrane transporter activity
- Specific Function
- Plays a role in the control of regulated secretion in neural and endocrine cells, enhancing selectively low-frequency neurotransmission. Positively regulates vesicle fusion by maintaining the readi...
- Gene Name
- SV2A
- Uniprot ID
- Q7L0J3
- Uniprot Name
- Synaptic vesicle glycoprotein 2A
- Molecular Weight
- 82694.665 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Blocker
- General Function
- Voltage-gated calcium channel activity
- Specific Function
- Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
- Gene Name
- CACNA1B
- Uniprot ID
- Q00975
- Uniprot Name
- Voltage-dependent N-type calcium channel subunit alpha-1B
- Molecular Weight
- 262493.84 Da
References
- Lukyanetz EA, Shkryl VM, Kostyuk PG: Selective blockade of N-type calcium channels by levetiracetam. Epilepsia. 2002 Jan;43(1):9-18. [Article]
- Martella G, Bonsi P, Sciamanna G, Platania P, Madeo G, Tassone A, Cuomo D, Pisani A: Seletracetam (ucb 44212) inhibits high-voltage-activated Ca2+ currents and intracellular Ca2+ increase in rat cortical neurons in vitro. Epilepsia. 2009 Apr;50(4):702-10. doi: 10.1111/j.1528-1167.2008.01915.x. Epub 2008 Dec 4. [Article]
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Binding
- General Function
- Transmitter-gated ion channel activity
- Specific Function
- The glycine receptor is a neurotransmitter-gated ion channel. Binding of glycine to its receptor increases the chloride conductance and thus produces hyperpolarization (inhibition of neuronal firing).
Components:
References
- Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Perucca E, Tomson T: Progress report on new antiepileptic drugs: a summary of the Eigth Eilat Conference (EILAT VIII). Epilepsy Res. 2007 Jan;73(1):1-52. Epub 2006 Dec 8. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Uesawa Y, Takeuchi T, Mohri K: Integrated analysis on the physicochemical properties of dihydropyridine calcium channel blockers in grapefruit juice interactions. Curr Pharm Biotechnol. 2012 Jul;13(9):1705-17. [Article]
Drug created at November 18, 2007 18:28 / Updated at February 03, 2022 21:01