Chemistry:Remacemide

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Short description: Chemical compound
Remacemide
Remacemide.svg
Clinical data
Trade namesEcovia[1]
Other names(±)-2-amino-N-[1,2-di(phenyl)propan-2-yl]acetamide PR 934-423
Routes of
administration		By mouth
ATC code
  • none
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC17H20N2O
Molar mass268.360 g·mol−1
3D model (JSmol)
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Remacemide is a drug which acts as a low-affinity NMDA antagonist with sodium channel blocking properties.[2] It has been studied for the treatment of acute ischemic stroke,[3][4] epilepsy,[5] Huntington's disease, and Parkinson's disease.

Because remacemide has only a modest effect on seizure frequency and causes dizziness, it is no longer believed that remacemide will be an effective treatment for epilepsy.[6] Although no such statement has been made about remacemide's potential for treating stroke, Huntington's, or Parkinson's, remacemide is no longer being developed for these conditions.[citation needed]

Remacemide is also known as remacemide hydrochloride, (±)-2-amino-N-(1-methyl-1,2-diphenylethyl)-acetamide hydrochloride, or FPL 12924AA.[7]

Adverse effects

Lack of adverse effects

Unlike many other treatments for epilepsy, remacemide does not appear to impair cognitive performance[9][10][5] or driving performance[11] in humans, although the evidence for effects on cognitive performance in animals has been mixed.[12][13][14][15][16] Remacemide is not a sedative.[17]

Toxicity

The median toxic dose of remacemide for neural impairment tests in mice is 5.6 mg/kg.[17] Its estimated median lethal dose is about 927.3 mg/kg in mice.[17] It has a favorable therapeutic index of 28.1 in mice.[17]

Drug interactions

Levodopa

Remacemide delays the absorption of levodopa (300 mg of remacemide one hour before levodopa treatment delays mean time to peak levodopa plasma concentration by 20%) but not its total absorption (area-under-the-curve for levodopa plasma concentration was unchanged).[18]

Sodium valproate

Remacemide does not interact with sodium valproate, a treatment for epilepsy.[19]

Carbamazepine

Ramacemide does interact with carbamazepine. Remacemide inhibits the metabolism of carbamazepine, while carbamazepine induces the metabolism of remacemide and FPL 12495.[20]

Alcohol

Remacemide salts

Remacemide is most commonly synthesized as the salt remacemide hydrochloride. However, there has been some investigation into other remacemide salts and their crystals, as different remacemide salts might taste more pleasant or have a solubility more suitable for a pediatric suspension formulation.[21]

Mechanism of action

Remacemide binds weakly and noncompetitively to the ionic channel site of the NMDA receptor complex.[7] Remacemide binds both allosterically and in the channel.[22] However, because remacemide binds so weakly to NMDAR, much of remacemide's in vivo effect against excitotoxicity is thought to be caused by its metabolic transformation to the more potent desglycine derivative FPL 12495.[7] That is, remacemide may actually act as a prodrug to deliver the active metabolite FPL 12495 to the central nervous system.[23]

Epilepsy

In a well validated and described genetic model of absence epilepsy, rats of the WAG/Rij strain, remacemide and its metabolite FPL 12495 were found to have a common for glutamate antagonist usual effect on the number of spike/wave dischargesEEG, the drugs decrease spike/wave discharges dose dependently. However, in contrast to most other glutamate antagonists, FPL 12495 increased the duration of the spike-wave discharges.[24]

Pharmacokinetics

Blood–brain barrier

The brain uptake index (BUI), a measure of a drug's ability to pass the blood–brain barrier that involves the injection of radiolabeled test and reference substances into the common carotid artery of anesthetized animals,[25][26] for remacemide is 51 ± 0.9 SD.[23]

Enantiomers

The (-)stereoisomer of remacemide is of equal potency to the racemic mixture in preventing maximal electroshock seizures when administered orally to rats, while the (+)stereoisomer is less potent.[27]

Metabolites

FPL 12495

Much of remacemide's effect in vivo is thought to be caused by the desglycine derivative FPL 12495 (±).[7] FPL 12495 (±) binds specifically and non-competitively to NMDAR.[28] Its effect on maximal electroconvulsive shock is more potent than remacemide.[7] The S isomer (FPL 12859) is even more potent than the racemic mixture, while the R isomer is less potent than the racemate.[7]

FPL 12495 is sometimes referred to as ARL 12495AA.[29][30][31]

Other metabolites

FPL 15053

FPL 15053 is the N-hydroxy-desglycinate of remacemide, and exhibits modest binding to NMDAR and modest effects on convulsions and mortality in test mice and rats.[7]

FPL 14331 and FPL 14465

FPL 14331 and FPL 14465 are the p-hydroxy-desglycinates of remacemide, and they exhibit some efficacy against maximal electroconvulsive shock after i.p. and i.v. dosing.[7]

FPL 15455

FPL 15455 is an oxoacetate metabolite of remacemide, but has no demonstrated biological activity.[7]

FPL 14991 and FPL 14981

FPL 14991 and FPL 14981 are both β-Miydroxy-desglycinates of remacemide, and they display modest efficacy against maximal electroconvulsive shock in mice.[7] However FPL 14981 and not FPL 14991 prevents NMDLA-induced convulsions and mortality in mice.[7]

FPL 13592 and FPL 15112

The hydroxy-methyl derivative of remacemide (FPL 13592) and its desglycinate (FPL 15112) prevents electric shock-induced convulsions only after i.v. administration; only the desglycine derivative binds to NMDAR.[7]

FPL 14467

FPL 14467 (p-dihydroxy-desglycine) is inactive in vivo and weak in binding NMDAR.[7]

Pharmacodynamics

The values for 50% displacement of [3H]MK801 were 68 μM for remacemide and 0.48 μM for FPL 12495AA.[7]

History

Current status

Remacemide is an experimental drug most recently being developed by the British multinational pharmaceutical company AstraZeneca. However, there has been little news of its progress since 2000. A few sources indicate that its development has been discontinued.[32][33]

Changing hands

Remacemide was one of the last drugs under development by the now-defunct English pharmaceutical company Fisons.[34] In 1995, it was acquired along with most of Fisons' research and development operations by the Swedish pharmaceutical company Astra,[35] which in 1999 merged with the British company Zeneca to form AstraZeneca.[36] In 2000, AstraZeneca considered possibly licensing out remacemide to some other pharmaceutical company,[37] but there has been little news about remacemide since then. Remacemide's development may have been discontinued in July 2001.[33]

Discovery and development under Fisons

In 1990, researchers at Fisons found that remacemide acted as an anticonvulsant in mice and rats[17][27] .[38] Because of remacemide's potential as a neuroprotective agent through preventing glutamate toxicity, it was soon also under investigation as a treatment for Huntington's disease[39] and Parkinson's disease.[40]

Astra

By 1995, when Astra acquired remacemide, it was already in Phase IIb clinical development as an anti-epileptic drug[35] and Phase I clinical development as a treatment for Huntington's .[39][41]

AstraZeneca

By 1998, when Astra announced its merger with Zeneca, remacemide had progressed to Phase III trials for epilepsy and Phase II trials for Parkinson's disease, and Astra was also investigating its potential for treating neuropathic pain[42]

In 1999, after the merger, AstraZeneca reported that they were investigating remacemide for its neuroprotective effects, and that they planned regulatory submissions for Huntington's disease in 2001 and for Parkinson's disease and epilepsy in 2003.[43]

Remacemide, under the trade name Ecovia, was designated an orphan drug for the treatment of Huntington's disease by the FDA in March 2000.[1]

Remacemide was last mentioned in AstraZeneca's reports on its R&D pipeline in 2000, when it was in Phase III clinical trials for remacemide in the treatment of Huntington's disease and Phase II for treatment of Parkinson's disease. At that time, the submission of the New Drug Application (NDA) to the FDA and the Marketing Authorization Application to the CHMP was projected for Huntington's in 2001 and for Parkinson's after 2003,[37] but there has been no news of such submission. In this report, it was also noted that remacemide was "under strategic review and a potential candidate for licensing activity"[37] (see this external article about drug licensing.)

Current news

There are no clinical trials of remacemide in progress, according to the Huntington Study Group,[44] and the Parkinson Study Group.[45]

Availability

Remacemide is an experimental drug not available to the public and not currently undergoing clinical trials.

See also

References

  1. ↑ 1.0 1.1 FDA (2009-05-05). "Cumulative List of all Products that have received Orphan Designation" (excel document). FDA. https://www.fda.gov/downloads/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/UCM162066.xls.&ei=1rGaT8mBBsPe0QGwobWLDw&usg=AFQjCNEhWBsqoIwuoHkskBhX8qHLA_UB2g. 
  2. ↑ "Na(+) channel effects of remacemide and desglycinyl-remacemide in rat cortical synaptosomes". European Journal of Pharmacology 438 (1–2): 63–8. March 2002. doi:10.1016/S0014-2999(02)01297-9. PMID 11906711. 
  3. ↑ "Initial experience with remacemide hydrochloride in patients with acute ischemic stroke". Annals of the New York Academy of Sciences 765 (1 Neuroprotecti): 322–3. September 1995. doi:10.1111/j.1749-6632.1995.tb16602.x. PMID 7486631. Bibcode: 1995NYASA.765..322M. 
  4. ↑ "Remacemide hydrochloride: a double-blind, placebo-controlled, safety and tolerability study in patients with acute ischemic stroke". Stroke 30 (9): 1796–801. September 1999. doi:10.1161/01.STR.30.9.1796. PMID 10471426. 
  5. ↑ 5.0 5.1 "The cognitive and psychomotor effects of remacemide and carbamazepine in newly diagnosed epilepsy". Epilepsy & Behavior 14 (3): 522–8. March 2009. doi:10.1016/j.yebeh.2008.11.012. PMID 19111629. 
  6. ↑ 6.0 6.1 "Remacemide for drug-resistant localization related epilepsy". The Cochrane Database of Systematic Reviews (4): CD001900. 2002. doi:10.1002/14651858.CD001900. PMID 12519561. 
  7. ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 "Biological profile of the metabolites and potential metabolites of the anticonvulsant remacemide". Epilepsy Research 12 (1): 9–20. June 1992. doi:10.1016/0920-1211(92)90086-9. PMID 1388119. 
  8. ↑ 8.0 8.1 "A multicenter randomized controlled trial of remacemide hydrochloride as monotherapy for PD. Parkinson Study Group". Neurology 54 (8): 1583–8. April 2000. doi:10.1212/wnl.54.8.1583. PMID 10762497. 
  9. ↑ "Cognitive function is unaffected by remacemide at therapeutic relevant single doses". J Psychopharmacol 12 (A41). 1998. 
  10. ↑ "Remacemide does not affect cognitive function following multiple dosing". J Psychopharmacol 12 (A41). 1998. 
  11. ↑ "A comparative study of the effects of carbamazepine and the NMDA receptor antagonist remacemide on road tracking and car-following performance in actual traffic". Psychopharmacology 159 (2): 203–10. January 2002. doi:10.1007/s002130100898. PMID 11862350. 
  12. ↑ "Behavioral effects associated with chronic ketamine or remacemide exposure in rats". Neurotoxicology and Teratology 29 (3): 348–59. May–Jun 2007. doi:10.1016/j.ntt.2006.12.004. PMID 17291718. 
  13. ↑ "Differential effects of two NMDA receptor antagonists on cognitive-behavioral development in nonhuman primates I". Neurotoxicology and Teratology 23 (4): 319–32. 1 July 2001. doi:10.1016/S0892-0362(01)00156-8. PMID 11485835. https://zenodo.org/record/1260115. 
  14. ↑ "Differential effects of two NMDA receptor antagonists on cognitive--behavioral performance in young nonhuman primates II". Neurotoxicology and Teratology 23 (4): 333–47. 1 July 2001. doi:10.1016/S0892-0362(01)00138-6. PMID 11485836. https://zenodo.org/record/1260113. 
  15. ↑ "Assessing the potential toxicity of MK-801 and remacemide: chronic exposure in juvenile rhesus monkeys". Neurotoxicology and Teratology 24 (2): 193–207. 1 March 2002. doi:10.1016/S0892-0362(02)00206-4. PMID 11943507. https://zenodo.org/record/1260117. 
  16. ↑ "Chronic exposure to NMDA receptor and sodium channel blockers during development in monkeys and rats: long-term effects on cognitive function". Annals of the New York Academy of Sciences 993 (1): 116–22; discussion 123–4. May 2003. doi:10.1111/j.1749-6632.2003.tb07519.x. PMID 12853303. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 "Preclinical profile of remacemide: a novel anticonvulsant effective against maximal electroshock seizures in mice". Epilepsy Research 7 (1): 11–28. Sep–Oct 1990. doi:10.1016/0920-1211(90)90050-6. PMID 1963406. 
  18. ↑ "The impact of remacemide hydrochloride on levodopa concentrations in Parkinson's disease. Parkinson Study Group". Clinical Neuropharmacology 22 (4): 220–5. Jul–Aug 1999. PMID 10442252. 
  19. ↑ "Lack of pharmacokinetic interaction between remacemide hydrochloride and sodium valproate in epileptic patients". Seizure 6 (3): 179–84. June 1997. doi:10.1016/S1059-1311(97)80003-9. PMID 9203245. 
  20. ↑ "Mutual interaction between remacemide hydrochloride and carbamazepine: two drugs with active metabolites". Epilepsia 37 (11): 1100–6. November 1996. doi:10.1111/j.1528-1157.1996.tb01031.x. PMID 8917061. 
  21. ↑ "Hydrophobic vs. Hydrophilic: Ionic Competition in Remacemide Salt Structures". Crystal Growth & Design 5 (2): 427–438. 1 March 2005. doi:10.1021/cg049836u. 
  22. ↑ "Block of the N-methyl-D-aspartate receptor by remacemide and its des-glycine metabolite". The Journal of Pharmacology and Experimental Therapeutics 276 (1): 161–8. January 1996. PMID 8558426. 
  23. ↑ 23.0 23.1 "Brain uptake and biotransformation of remacemide hydrochloride, a novel anticonvulsant". Drug Metabolism and Disposition 22 (3): 443–6. May–Jun 1994. PMID 8070322. 
  24. ↑ "Effects of remacemide and its metabolite FPL 12495 on spike-wave discharges, electroencephalogram and behaviour in rats with absence epilepsy". Neuropharmacology 34 (4): 419–25. April 1995. doi:10.1016/0028-3908(95)00008-T. PMID 7566473. 
  25. ↑ "Estimation of cerebral extraction of circulating compounds by the brain uptake index method: influence of circulation time, volume injection, and cerebral blood flow". Acta Physiologica Scandinavica 107 (2): 153–9. October 1979. doi:10.1111/j.1748-1716.1979.tb06455.x. PMID 525379. 
  26. ↑ "Measurement of cerebral glucose utilization using washout after carotid injection in the rat". Journal of Neurochemistry 38 (5): 1413–8. May 1982. doi:10.1111/j.1471-4159.1982.tb07920.x. PMID 7062059. 
  27. ↑ 27.0 27.1 "Preclinical profile of the anticonvulsant remacemide and its enantiomers in the rat". Epilepsy Research 9 (3): 161–74. September 1991. doi:10.1016/0920-1211(91)90050-p. PMID 1660399. 
  28. ↑ "The effect of the desglycinyl metabolite of remacemide on cortical wedges prepared from DBA/2 mice". European Journal of Pharmacology 287 (3): 251–6. December 1995. doi:10.1016/0014-2999(95)00500-5. PMID 8991798. 
  29. ↑ "Electrophysiological effects of the anticonvulsant remacemide hydrochloride and its metabolite ARL 12495AA on rat CA1 hippocampal neurons in vitro". Neuropharmacology 36 (7): 951–9. July 1997. doi:10.1016/S0028-3908(97)00069-5. PMID 9257939. 
  30. ↑ "Neurochemical actions of the desglycinyl metabolite of remacemide hydrochloride (ARL 12495AA) in mouse brain". British Journal of Pharmacology 121 (5): 923–6. July 1997. doi:10.1038/sj.bjp.0701219. PMID 9222548. 
  31. ↑ "The stereo-isomers of the anticonvulsant ARL 12495AA limit sustained repetitive firing and modify action potential properties of rat hippocampal neurons in vitro". The Journal of Pharmacology and Experimental Therapeutics 281 (3): 1191–8. June 1997. PMID 9190853. 
  32. ↑ "remacemide () UKMi New Drugs Online Database". http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=2781. 
  33. ↑ 33.0 33.1 "remacemide AstraZeneca discontinued, Europe, USA, Canada (epilepsy)". R & D Focus Drug News. March 15, 2004. http://business.highbeam.com/436989/article-1G1-114382356/remacemide-astrazeneca-discontinued-europe-usa-canada. 
  34. ↑ "FISONS DISCONTINUES TIPREDANE DEV'T". the pharma letter. 12 April 1993. http://www.thepharmaletter.com/file/34535/fisons-discontinues-tipredane-devt.html. 
  35. ↑ 35.0 35.1 "Sweden's Astra Buys Most Of Fisons R&D Ops". the pharma letter. 27 March 1995. http://www.thepharmaletter.com/file/40335/swedens-astra-buys-most-of-fisons-rd-ops.html. 
  36. ↑ "AstraZeneca History". AstraZeneca. http://www.astrazeneca.com/About-Us/History. 
  37. ↑ 37.0 37.1 37.2 "AstraZeneca R&D Pipeline: NCEs". AstraZeneca. 2000. http://www.astrazeneca.com/cs/Satellite?blobcol=urldata&blobheader=application%2Fpdf&blobheadername1=Content-Disposition&blobheadername2=MDT-Type&blobheadervalue1=inline%3B+filename%3DR%26amp%3BD-Pipeline-table.pdf&blobheadervalue2=abinary%3B+charset%3DUTF-8&blobkey=id&blobtable=MungoBlobs&blobwhere=1285616469893&ssbinary=true. 
  38. ↑ "Status of PR 934-423, a novel anticonvulsant targeted for generalized tonic/clonic seizures (new designation is FPL 12924AA)". Progress in Clinical and Biological Research 361: 435–41. 1990. PMID 2290849. 
  39. ↑ 39.0 39.1 "A controlled trial of remacemide hydrochloride in Huntington's disease". Movement Disorders 11 (3): 273–7. May 1996. doi:10.1002/mds.870110310. PMID 8723144. 
  40. ↑ "Antiparkinsonian effects of remacemide hydrochloride, a glutamate antagonist, in rodent and primate models of Parkinson's disease". Annals of Neurology 35 (6): 655–61. June 1994. doi:10.1002/ana.410350605. PMID 8210221. 
  41. ↑ "Completed Clinical Trials". Huntington Study Group. 2010. http://www.huntington-study-group.org/ClinicalResearch/CompletedClinicalTrials/tabid/65/Default.aspx. 
  42. ↑ "Astra 98 Annual Report". Stellan Ståls Grafiska AB. http://reports.huginonline.com/hugin/756071.pdf. 
  43. ↑ Polinsky, Ron. "AstraZeneca CNS". AstraZeneca. http://www.astrazeneca.com/cs/Satellite?blobcol=urldata&blobheader=application%2Fpdf&blobheadername1=Content-Disposition&blobheadername2=MDT-Type&blobheadervalue1=inline%3B+filename%3DCNS---Ron-Polinsky.pdf&blobheadervalue2=abinary%3B+charset%3DUTF-8&blobkey=id&blobtable=MungoBlobs&blobwhere=1285616440467&ssbinary=true. 
  44. ↑ "Clinical Trials and Observational Studies in Progress". Huntington Study Group. 2010. http://www.huntington-study-group.org/ClinicalResearch/ClinicalTrialsObservationalStudiesinProgress/tabid/81/Default.aspx. 
  45. ↑ "Clinical Trials in Progress - Parkinson Study Group". http://www.parkinson-study-group.org/parkinson-research/clinical-trials-in-progess/. 

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