Identification

Name
Seletracetam
Accession Number
DB05885  (DB12175)
Type
Small Molecule
Groups
Investigational
Description

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.

Structure
Thumb
Synonyms
  • (2S)-2-((4S)-4-(2,2-Difluoroethenyl)-2-oxopyrrolidin-1-yl)butanamide
External IDs
UCB 44212 / UCB-44212
Categories
UNII
RFR2CH3QZK
CAS number
357336-74-4
Weight
Average: 232.2272
Monoisotopic: 232.102334112
Chemical Formula
C10H14F2N2O2
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

Pharmacology

Indication

Investigated for use/treatment in epilepsy.

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 [A19305].

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.

TargetActionsOrganism
ASynaptic vesicle glycoprotein 2A
modulator
Human
AVoltage-dependent N-type calcium channel subunit alpha-1B
blocker
Human
UGlycine receptor (alpha-1/beta)
binding
Human
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.

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.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Seletracetam.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Seletracetam.
2,4-thiazolidinedioneThe risk or severity of hypoglycemia can be increased when Seletracetam is combined with 2,4-thiazolidinedione.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Seletracetam.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Seletracetam.
5-androstenedioneThe metabolism of Seletracetam can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Seletracetam can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Seletracetam.
AbafunginThe therapeutic efficacy of Abafungin can be increased when used in combination with Seletracetam.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Seletracetam.
Food Interactions
Not Available

References

Synthesis Reference
  1. Wong MG, Defina JA, Andrews PR: Conformational analysis of clinically active anticonvulsant drugs. Journal of Medical Chemistry 1986 (29): 562-72. [PubMed: 3959032]
  2. 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]
  3. 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
  1. Bennett B, Matagne A, Michel P, Leonard M, Cornet M, Meeus MA, Toublanc N: Seletracetam (UCB 44212). Neurotherapeutics. 2007 Jan;4(1):117-22. [PubMed:17199025]
  2. Bialer M: New antiepileptic drugs that are second generation to existing antiepileptic drugs. Expert Opin Investig Drugs. 2006 Jun;15(6):637-47. [PubMed:16732716]
  3. 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. [PubMed:16556440]
  4. 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. [PubMed:23214383]
  5. 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. [PubMed:20167814]
  6. Luszczki JJ: Third-generation antiepileptic drugs: mechanisms of action, pharmacokinetics and interactions. Pharmacol Rep. 2009 Mar-Apr;61(2):197-216. [PubMed:19443931]
  7. 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
Wikipedia
Seletracetam

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedNot AvailableEpilepsy, Localization Related2
2, 3WithdrawnTreatmentEpilepsy, Localization Related1
3WithdrawnNot AvailableEpilepsies1
3WithdrawnTreatmentEpilepsies1

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
PropertyValueSource
Water Solubility1.02 mg/mLALOGPS
logP0.51ALOGPS
logP0.091ChemAxon
logS-2.4ALOGPS
pKa (Strongest Acidic)14.66ChemAxon
pKa (Strongest Basic)-0.75ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area63.4 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity64.33 m3·mol-1ChemAxon
Polarizability21.1 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9859
Caco-2 permeable-0.5795
P-glycoprotein substrateSubstrate0.5226
P-glycoprotein inhibitor IInhibitor0.5203
P-glycoprotein inhibitor IINon-inhibitor0.9211
Renal organic cation transporterNon-inhibitor0.7747
CYP450 2C9 substrateNon-substrate0.8933
CYP450 2D6 substrateNon-substrate0.8178
CYP450 3A4 substrateSubstrate0.5193
CYP450 1A2 substrateNon-inhibitor0.7893
CYP450 2C9 inhibitorNon-inhibitor0.7033
CYP450 2D6 inhibitorNon-inhibitor0.9242
CYP450 2C19 inhibitorNon-inhibitor0.6378
CYP450 3A4 inhibitorNon-inhibitor0.8864
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8343
Ames testNon AMES toxic0.6472
CarcinogenicityNon-carcinogens0.839
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6055 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9688
hERG inhibition (predictor II)Non-inhibitor0.7837
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Alpha-amino acid or derivatives / Fatty amide / Fatty acyl / Pyrrolidone / 2-pyrrolidone / N-alkylpyrrolidine / Pyrrolidine / Tertiary carboxylic acid amide / Carboxamide group / Ketene acetal or derivatives
show 19 more
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
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
  1. Bennett B, Matagne A, Michel P, Leonard M, Cornet M, Meeus MA, Toublanc N: Seletracetam (UCB 44212). Neurotherapeutics. 2007 Jan;4(1):117-22. [PubMed:17199025]
  2. Pollard JR: Seletracetam, a small molecule SV2A modulator for the treatment of epilepsy. Curr Opin Investig Drugs. 2008 Jan;9(1):101-7. [PubMed:18183537]
Kind
Protein
Organism
Human
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
  1. Lukyanetz EA, Shkryl VM, Kostyuk PG: Selective blockade of N-type calcium channels by levetiracetam. Epilepsia. 2002 Jan;43(1):9-18. [PubMed:11879381]
  2. 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. [PubMed:19055493]
Kind
Protein group
Organism
Human
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
  1. 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. [PubMed:17158031]

Enzymes

Kind
Protein
Organism
Human
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
  1. 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. [PubMed:22039822]

Drug created on November 18, 2007 11:28 / Updated on November 02, 2018 06:12