Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Seletracetam: Difference between pages

{{Short description|Chemical compound}}

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| Verifiedfields = changed

| verifiedrevid = 464388926

| IUPAC_name = (2''S'')-2-[(4''R'')-4-(2,2-Difluoroethenyl)-2-oxo-pyrrolidin-1-yl]butanamide<ref name=Malykh />

| width = 140

| legal_AU = S4

| legal_US = Unscheduled

| routes_of_administration = Oral<ref name=Malykh /><ref name="Bennett" />

| bioavailability = >90%<ref name=Malykh /><ref name="Bennett" />

| elimination_half-life = 8 hours<ref name=Malykh /><ref name="Bennett" />

| excretion =

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 357336-74-4

'''Seletracetam''' (UCB 44212) is a [[2-pyrrolidone|pyrrolidone]]-derived<ref name="Bennett" /> [[drug]] of the [[racetam]] family that is structurally related to [[levetiracetam]] (trade name Keppra).<ref name="Bennett" /><ref name=Pollard /> It was under [[drug development|development]] by UCB Pharmaceuticals as a more potent and effective [[anticonvulsant]] drug to replace [[levetiracetam]] but its development has been halted.<ref name=Malykh />

There are two main mechanisms of action for seletracetam. The first is its high-affinity [[stereospecificity|stereospecific]] binding to synaptic vesicle glycoprotein 2A ([[SV2A]]).<ref name="Bennett" /><ref name=Pollard>{{cite journal | vauthors = Pollard JR | title = Seletracetam, a small molecule SV2A modulator for the treatment of epilepsy | journal = Current Opinion in Investigational Drugs | volume = 9 | issue = 1 | pages = 101–107 | date = January 2008 | pmid = 18183537 }}</ref> Seletracetam has shown potent seizure suppression in models of acquired and genetic epilepsy,<ref name=Pollard /> and has been well tolerated by various animal models.<ref name=Pollard /> The second is its binding to [[N-type calcium channel]]s and preventing influx of [[calcium in biology|Ca²⁺]] during high-voltage activation that is typical of [[epilepsy]].<ref name=Martella /><ref name=Pisani2004 /><ref name=Custer/>

While similar in structure to [[nootropic]] drugs, it is not expected to have cognitive enhancing properties.<ref name=Matagne /> Seletracetam was in Phase II [[clinical trials]] under the supervision of the U.S. [[Food and Drug Administration]] (FDA) but its production is on hold.<ref name=Pollard />

==Synthesis==

Seletracetam's molecular structure contains elements common to other [[anticonvulsants]], including [[levetiracetam]] and [[brivaracetam]], such as a nitrogen heterocyclic system.<ref>{{cite journal | vauthors = Wong MG, Defina JA, Andrews PR | title = Conformational analysis of clinically active anticonvulsant drugs | journal = Journal of Medicinal Chemistry | volume = 29 | issue = 4 | pages = 562–572 | date = April 1986 | pmid = 3959032 | doi = 10.1021/jm00154a022 }}</ref><ref>{{cite journal | vauthors = Bruno-Blanch L, Gálvez J, García-Domenech R | title = Topological virtual screening: a way to find new anticonvulsant drugs from chemical diversity | journal = Bioorganic & Medicinal Chemistry Letters | volume = 13 | issue = 16 | pages = 2749–2754 | date = August 2003 | pmid = 12873507 | doi = 10.1016/S0960-894X(03)00535-3 }}</ref> Like [[brivaracetam]], seletracetam is a derivative of [[levetiracetam]].

Structure and activity relationship studies have concluded that the most potent anticonvulsant activity was at the [[amide]] nitrogen atom and that this activity was further enhanced by nearby [[electronegative]] [[functional group]]s such as the di-fluoro group on seletracetam.<ref>{{cite journal | vauthors = Kamiński K, Rzepka S, Obniska J | title = Synthesis and anticonvulsant activity of new 1-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]pyrrolidine-2,5-diones | journal = Bioorganic & Medicinal Chemistry Letters | volume = 21 | issue = 19 | pages = 5800–5803 | date = October 2011 | pmid = 21875804 | doi = 10.1016/j.bmcl.2011.07.118 }}</ref>

==Administration==

Seletracetam is an orally administered drug, after which it is quickly and efficiently absorbed.<ref name = "Bennett">{{cite journal | vauthors = Bennett B, Matagne A, Michel P, Leonard M, Cornet M, Meeus MA, Toublanc N | title = Seletracetam (UCB 44212) | journal = Neurotherapeutics | volume = 4 | issue = 1 | pages = 117–122 | date = January 2007 | pmid = 17199025 | pmc = 7479702 | doi = 10.1016/j.nurt.2006.11.014 | doi-access = free }}</ref> The typical dosage is 0.03–10&nbsp;mg/kg per day (up to 0.6g per day).<ref name=Malykh>{{cite journal | vauthors = Malykh AG, Sadaie MR | title = Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders | journal = Drugs | volume = 70 | issue = 3 | pages = 287–312 | date = February 2010 | pmid = 20166767 | doi = 10.2165/11319230-000000000-00000 | s2cid = 12176745 }}</ref>

==Mechanism of action==

Seletracetam's anti-epileptic effects are due to its high affinity binding to synaptic vesicle glycoprotein 2A ([[SV2A]])<ref name=Malykh /><ref name="Bennett" /><ref name=Pollard />—part of a [[calcium in biology|calcium ion]] regulator. The [[SV2A]] protein assists with the coordination of synaptic vesicle exocytosis,<ref name=Bialer /><ref name=Crowder>{{cite journal | vauthors = Crowder KM, Gunther JM, Jones TA, Hale BD, Zhang HZ, Peterson MR, Scheller RH, Chavkin C, Bajjalieh SM | display-authors = 6 | title = Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A) | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 26 | pages = 15268–15273 | date = December 1999 | pmid = 10611374 | pmc = 24809 | doi = 10.1073/pnas.96.26.15268 | doi-access = free | bibcode = 1999PNAS...9615268C }}</ref> which induces [[neurotransmitter]] release in the presence of an influx in [[calcium in biology|Ca²⁺]]. A correlation has been drawn between the binding affinity of seletracetam (and its analogues) to [[SV2A]] and the degree of seizure prevention in animal models.<ref name=Matagne>{{cite journal | vauthors = Matagne A, Margineanu DG, Potschka H, Löscher W, Michel P, Kenda B, Klitgaard H | title = Profile of the new pyrrolidone derivative seletracetam (ucb 44212) in animal models of epilepsy | journal = European Journal of Pharmacology | volume = 614 | issue = 1–3 | pages = 30–37 | date = July 2009 | pmid = 19383493 | doi = 10.1016/j.ejphar.2009.04.024 }}</ref><ref name=Bialer /><ref name=Lynch />

In addition, studies of ion currents have shown that seletracetam significantly decreases the amount of high-voltage derived [[calcium in biology|Ca²⁺]] currents<ref name=Martella>{{cite journal | vauthors = Martella G, Bonsi P, Sciamanna G, Platania P, Madeo G, Tassone A, Cuomo D, Pisani A | display-authors = 6 | title = Seletracetam (ucb 44212) inhibits high-voltage-activated Ca2+ currents and intracellular Ca2+ increase in rat cortical neurons in vitro | journal = Epilepsia | volume = 50 | issue = 4 | pages = 702–710 | date = April 2009 | pmid = 19055493 | doi = 10.1111/j.1528-1167.2008.01915.x | s2cid = 9067249 | doi-access = free }}</ref> which have been implicated in causing the high intracellular [[calcium in biology|Ca²⁺]] influx during [[epileptic]] activity.<ref name=Pisani2004>{{cite journal | vauthors = Pisani A, Bonsi P, Martella G, De Persis C, Costa C, Pisani F, Bernardi G, Calabresi P | display-authors = 6 | title = Intracellular calcium increase in epileptiform activity: modulation by levetiracetam and lamotrigine | journal = Epilepsia | volume = 45 | issue = 7 | pages = 719–728 | date = July 2004 | pmid = 15230693 | doi = 10.1111/j.0013-9580.2004.02204.x | s2cid = 31781002 | doi-access = free }}</ref> It is thought that seletracetam binds to [[N-type calcium channel|N-type Ca²⁺ channels]] and inhibits their ability to allow calcium ions to enter the cell,<ref name=Martella /><ref name=Pisani2004 /> although the drug does not bind to [[T-type calcium channel|T-type channels]] that mediate low-voltage activated Ca²⁺ currents.<ref name="Bennett" /><ref name=Luszcki /> Seletracetam thereby decreases cellular excitation, but it does not seem to affect voltage-gated [[sodium|Na⁺]] or [[potassium|K⁺]] currents.<ref name=Martella /> Selectracetam has been demonstrated to not significantly affect currents gated by [[NMDA]], [[AMPA]], [[GABA]], [[glycine]], or [[kainic acid]].<ref name=Rigo>{{cite journal| vauthors = Faria LC, Silva AC, Priel MR, Naffah-Mazzacoratti MD, Mody I, Cavalheiro EA | title=Seletracetam (ucb 44212): effect on inhibitory and excitatory neurotransmission| journal=Epilepsia| year=2005| volume=46|issue=Suppl. 8|page=110|doi=10.1111/j.1528-1167.2005.460801_14.x|s2cid=221732819|doi-access=free}}</ref>

The dual effect of seletracetam is an overall decrease in the amount of [[calcium in biology|Ca²⁺]] influx in the cell during an [[action potential]] due to binding at [[N-type calcium channel|N-type channels]], which prevents over-excitation of the [[neuron]], as well as a decrease in [[neurotransmitter]] release as a product of cellular excitation due to the interaction of the drug with [[SV2A]], which reduces the spread of excitation to nearby cells.<ref name=Custer>{{cite journal | vauthors = Custer KL, Austin NS, Sullivan JM, Bajjalieh SM | title = Synaptic vesicle protein 2 enhances release probability at quiescent synapses | journal = The Journal of Neuroscience | volume = 26 | issue = 4 | pages = 1303–1313 | date = January 2006 | pmid = 16436618 | pmc = 6674579 | doi = 10.1523/JNEUROSCI.2699-05.2006 | doi-access = free }}</ref>

Compared to [[levetiracetam]], which binds at the same site,<ref name=Bialer>{{cite journal | vauthors = Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Perucca E, Tomson T | title = Progress report on new antiepileptic drugs: a summary of the Eighth Eilat Conference (EILAT VIII) | journal = Epilepsy Research | volume = 73 | issue = 1 | pages = 1–52 | date = January 2007 | pmid = 17158031 | doi = 10.1016/j.eplepsyres.2006.10.008 | s2cid = 45026113 }}</ref> seletracetam binds to [[SV2A]] with ten times higher affinity.<ref name=Matagne /><ref name=Lynch>{{cite journal | vauthors = Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, Fuks B | title = The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 26 | pages = 9861–9866 | date = June 2004 | pmid = 15210974 | pmc = 470764 | doi = 10.1073/pnas.0308208101 | doi-access = free | bibcode = 2004PNAS..101.9861L }}</ref>

The nature of why the seletracetam molecule binds so specifically to SV2A and how SV2A affects exocytosis is unclear.<ref>{{cite journal | vauthors = Pollard JR, French J | title = Antiepileptic drugs in development | journal = The Lancet. Neurology | volume = 5 | issue = 12 | pages = 1064–1067 | date = December 2006 | pmid = 17110287 | doi = 10.1016/S1474-4422(06)70627-5 | s2cid = 22569327 }}</ref>

==Pharmacokinetics==

The oral [[bioavailability]] of seletracetam is >90%<ref name="Bennett" /> and its [[biological half-life|half-life]] is approximately 8 hours.<ref name=Malykh /><ref name="Bennett" /> 25% of ingested seletracetam is metabolized and excreted unchanged and about 53% is excreted in the form of an inactive [[carboxylic acid]] metabolite.<ref name=Bialer /><ref name=Luszcki /> The main metabolic mechanism is the hydrolysis of an [[acetamide]] to a [[carboxylic acid]].<ref name=Luszcki /><ref name=Strolin>{{cite journal | vauthors = Strolin Benedetti M, Whomsley R, Nicolas JM, Young C, Baltes E | title = Pharmacokinetics and metabolism of 14C-levetiracetam, a new antiepileptic agent, in healthy volunteers | journal = European Journal of Clinical Pharmacology | volume = 59 | issue = 8–9 | pages = 621–630 | date = November 2003 | pmid = 14530892 | doi = 10.1007/s00228-003-0655-6 | s2cid = 25017909 }}</ref>

Seletracetam exhibits [[order of reaction|first-order]] mono-compartmental [[pharmacokinetics]], in which there is a simple linear relationship between the amount of drug that was administered, the time that has passed, and the amount of drug subsequently remaining in the body.<ref name="Bennett" /> This contrasts the nonlinear pharmacokinetics typical of previously available [[anticonvulsants]] such as [[phenobarbital]], phenytolin, [[valproate]] and [[carbamazepine]].<ref name="Bennett" /> The benefit of linear kinetics is that the steady-state concentration of the drug is directly and reliably related to the dose of the drug that is administered; this allows for simple and reliable dose adjustments.

==''In vitro'' studies==

''In vitro'' studies performed in rodent hippocampal slices found that seletracetam causes a complete reversal of the increases in activity of [[population spike]] [[amplitude]] in epilepsy models.<ref name =Matagne/> These reductions in ''in vitro'' epilepsy symptoms were present at [[extracellular fluid|extracellular]] concentrations of 3.2 μM.<ref name =Matagne/> This is approximately 10% of the most effective concentration of [[levetiracetam]] in similar tests.<ref>{{cite journal | vauthors = Margineanu DG, Klitgaard H | title = Inhibition of neuronal hypersynchrony in vitro differentiates levetiracetam from classical antiepileptic drugs | journal = Pharmacological Research | volume = 42 | issue = 4 | pages = 281–285 | date = October 2000 | pmid = 10987984 | doi = 10.1006/phrs.2000.0689 }}</ref>

==Animal studies==

Seletracetam has been tested on various [[animal models]] for epilepsy, with mixed results.

Unlike drugs that act on [[voltage-gated sodium channel]]s,<ref name="pmid16621450">{{cite journal | vauthors = Rogawski MA | title = Diverse mechanisms of antiepileptic drugs in the development pipeline | journal = Epilepsy Research | volume = 69 | issue = 3 | pages = 273–294 | date = June 2006 | pmid = 16621450 | pmc = 1562526 | doi = 10.1016/j.eplepsyres.2006.02.004 }}</ref> seletracetam was demonstrated to have no significant effect on the maximal electroshock seizure test results in mice.<ref name =Matagne/> It similarly had no relieving effects in mice of the other most common acute seizure model, the [[pentylenetetrazol]] convulsion-induction model.<ref name="Bennett" /><ref name =Matagne/><ref name=Luszcki />

Seletracetam did, however, show promising results in acquired and genetic epilepsy models.<ref name="Bennett" /><ref name =Matagne/> In the mouse model of corneal kindling, which exhibits the anticonvulsant capability of generalized motor seizures, doses as low as 0.07&nbsp;mg/kg [[intraperitoneal injection]] (i.p.), and [[Effective dose (pharmacology)|ED₅₀]] of 0.31&nbsp;mg/kg i.p. were effective.<ref name =Matagne/> Occurrence of audiogenic seizures—those induced by white noise—in mice were also significantly reduced by an [[Effective dose (pharmacology)|ED₅₀]] of 0.17&nbsp;mg/kg i.p., which suggests that selectracetam reduces convulsions caused by [[clonic seizures]].<ref name =Matagne/>

In hippocampal [[kindling model]] rats, seizure severity was significantly reduced by seletracetam oral doses of 0.23&nbsp;mg/kg. This provides further evidence of the potential benefits of selectracetam on generalized motor seizures.<ref name =Matagne/> Seletracetam also performed well as a method to reduce the suppression of spontaneous spike-and-wave discharges that are often associated with [[absence epilepsy]] activity.<ref name=Hughes>{{cite journal | vauthors = Hughes JR | title = Absence seizures: a review of recent reports with new concepts | journal = Epilepsy & Behavior | volume = 15 | issue = 4 | pages = 404–412 | date = August 2009 | pmid = 19632158 | doi = 10.1016/j.yebeh.2009.06.007 | s2cid = 22023692 }}</ref> This was demonstrated by its effect on Strasbourg genetic absence epilepsy rats (GAERS).<ref>{{cite conference |vauthors = Marescaux C, Vergnes M, Depaulis A |title=Genetic absence epilepsy in rats from Strasbourg — A review |veditors=Marescaux C, Vergnes M, Bernasconi R |book-title=Generalized Non-Convulsive Epilepsy: Focus on GABA-B Receptors |year=1992 |pages=37–69 |doi=10.1007/978-3-7091-9206-1_4 |isbn=978-3-211-82340-8}}</ref> This model had an [[Effective dose (pharmacology)|ED₅₀]] of 0.15&nbsp;mg/kg i.p.<ref name =Matagne/>

Rodents were found to have negligible behavioral deficits as a result of seletracetam administration, as measured by performance on a [[rotarod]] task.<ref name=Matagne/><ref>{{cite journal | vauthors = Stefan H, Steinhoff BJ | title = Emerging drugs for epilepsy and other treatment options | journal = European Journal of Neurology | volume = 14 | issue = 10 | pages = 1154–1161 | date = October 2007 | pmid = 17880570 | doi = 10.1111/j.1468-1331.2007.01706.x | s2cid = 41155699 }}</ref>

==Adverse effects and tolerance==

Unlike currently prescribed [[anticonvulsants]] such as phenytoin, [[valproate]], and [[phenobarbital]], seletracetam shows few [[central nervous system]] (CNS) side effects and is predicted to have low levels of drug-drug interactions due to its low binding (<10%) to plasma proteins.<ref name="Bennett" /><ref name = "Brodie">{{cite journal | vauthors = Brodie MJ | title = Do we need any more new antiepileptic drugs? | journal = Epilepsy Research | volume = 45 | issue = 1–3 | pages = 3–6 | date = May 2001 | pmid = 11461782 | doi = 10.1016/S0920-1211(01)00203-0 | s2cid = 37908949 }}</ref> There have been, however, no formal studies conducted on drug-drug interactions with seletracetam.<ref name=Bialer />

Other than [[SV2A]] and the high-voltage-activated Ca²⁺ channels, seletracetam does not significantly bind to other CNS receptors, ion channels, or uptake mechanisms.<ref name=Bialer /> Seletracetam has, however, shown a slight selectivity for glycine receptors.<ref name=Bialer /><ref name=Luszcki>{{cite journal | vauthors = Luszczki JJ | title = Third-generation antiepileptic drugs: mechanisms of action, pharmacokinetics and interactions | journal = Pharmacological Reports | volume = 61 | issue = 2 | pages = 197–216 | date = Mar–Apr 2009 | pmid = 19443931 | doi = 10.1016/s1734-1140(09)70024-6 | s2cid = 72918370 }}</ref><ref name=Bialer2004>{{cite journal | vauthors = Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Perucca E, Tomson T | title = Progress report on new antiepileptic drugs: a summary of the Seventh Eilat Conference (EILAT VII) | journal = Epilepsy Research | volume = 61 | issue = 1–3 | pages = 1–48 | date = Sep–Oct 2004 | pmid = 15570674 | doi = 10.1016/j.eplepsyres.2004.07.010 | s2cid = 1154454 }}</ref> This drug neither inhibits nor unnecessarily induces the action of any major human metabolizing enzymes, which further reduces adverse effects.<ref name=Brodie />

Early data from phase I trials were optimistic, and found seletracetam to be well tolerated by human volunteers.<ref>{{cite journal|vauthors=Leese PT, Goldwater DR, Hulhoven R, Salas E, Toublanc N, Chen D, Sargentini-Maier ML, Stockis A|display-authors=6|title=Seletracetam (UCB 44212): Single and Multiple Rising Dose Safety, Tolerability and Pharmacokinetics in Healthy Subjects|journal=American Epilepsy Society Abstracts|year=2006|pages=2.131|url=http://www.aesnet.org/go/publications/aes-abstracts/abstract-search/mode/display/st/leese/sy/2006/sb/All/id/6570|access-date=2012-05-15|archive-date=2013-10-29|archive-url=https://web.archive.org/web/20131029190516/http://www.aesnet.org/go/publications/aes-abstracts/abstract-search/mode/display/st/leese/sy/2006/sb/All/id/6570|url-status=dead}}</ref>

In phase II trials side effects were limited to the CNS in origin, were of mild to moderate severity, and most were resolved within 24 hours<ref name="Bennett" /> and with no medical intervention.<ref name=Bialer /> The most frequently reported adverse effects of seletracetam were dizziness, feeling drunk, euphoria, nausea, and [[somnolence]].<ref name=Bialer />

Seletracetam was well tolerated by healthy individuals after single oral doses ranging from 2 to 600&nbsp;mg, as well as after b.i.d. (twice daily) doses of 200&nbsp;mg.<ref name=Bialer /> [[Toxicology]] studies have shown that this drug has low acute oral toxicity and no significant negative effects on the CNS, cardiac, or respiratory systems.<ref name=Bialer /> High doses of 2000&nbsp;mg/kg per day (in mice and rats) and greater than 600&nbsp;mg/kg per day (in dogs) were poorly tolerated.<ref name=Bialer />

==FDA approval status==

Phase II [[clinical trials]] of seletracetam were ongoing but in July 2007 the company stated that the drug's development has been put on hold.<ref name=Pollard /> Although the conducted Phase II trials showed success, it was less than expected given the performance of seletracetam in animal models.<ref name=Malykh /> There have been no known Phase IIb or Phase III [[clinical trials|trials]].<ref name=Pollard />

In 2010, development of seletracetam was halted in favor of the development of [[brivaracetam]], a newer variation of the drug.<ref name=Malykh />

== References ==

{{Reflist|33em}}

{{Racetams}}

[[Category:Racetams]]

[[Category:Organofluorides]]

[[Category:Alkene derivatives]]

[[Category:Butyramides]]

[[Category:Abandoned drugs]]