Latrepirdine

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Latrepirdine
File:Dimebolin.svg
Systematic (IUPAC) name
2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-1H-pyrido(4,3-b)indole
Clinical data
Routes of
administration		 Oral
Legal status
Legal status
  • ℞ (Prescription only)
Identifiers
CAS Number 3613-73-8
ATC code none
PubChem CID 197033
ChemSpider 170644
Chemical data
Formula C21H25N3
Molar mass 319.443 g/mol[[Script error: No such module "String".]]
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Latrepirdine (INN, also known as dimebolin and sold as Dimebon), is an antihistamine drug which has been used clinically in Russia since 1983.[1]

Research is continuing in both Russia and western nations into potential applications as a neuroprotective drug to combat Alzheimer's disease and, possibly, as a nootropic as well.[2] However, a Phase III clinical trial for Alzheimer's disease treatment failed to show any benefit.[3]

Uses

Latrepirdine is an orally-active small molecule compound that has been shown to inhibit brain cell death in preclinical studies of Alzheimer's disease and Huntington's disease, making it a potential treatment for these and other neurodegenerative diseases. Research suggests that it may also have cognition-enhancing effects in healthy individuals, in the absence of neurodegenerative disease pathology.[4]

Alzheimer's disease

Recently latrepirdine has attracted renewed interest after being shown to have positive effects on persons suffering from Alzheimer’s disease. Animal studies showing potential beneficial effects on Alzheimer's disease models were shown in Russian research in 2000.[5] Preliminary results from human trials have also been promising. In an initial six-month phase II trial, results have shown that at 12 months there was significant improvement over placebo.[6] Latrepirdine showed promising results in a Phase III equivalent double blind trial in Russia with mild–moderate stage patients.[7][8]

In April 2009, Pfizer and Medivation initiate a phase III trial (CONCERT study) aiming for FDA approval.[9] In March 2010, Pfizer announced that this clinical trial failed to show any benefit for the treatment of Alzheimer's disease patients.[3]

Numerous phase III trials for AD were recruiting in 2009.[10][11][12][13]

In July 2009 Pfizer and Medivation announced that latrepirdine will be the proposed international nonproprietary name for latrepirdine for the treatment of Alzheimer's.[14]

In March 2010 the results of a clinical trial phase III were released. It was announced that the investigational Alzheimer's disease drug dimebon failed in the pivotal CONNECTION trial of patients with mild-to-moderate disease.[15]

Pharmacology

Latrepirdine appears to operate through multiple mechanisms of action, both blocking the action of neurotoxic beta-amyloid proteins and inhibiting L-type calcium channels,[16] modulating the action of AMPA and NMDA glutamate receptors,[17] and may exert a neuroprotective effect by blocking a novel target that involves mitochondrial pores,[18] which are believed to play a role in the cell death that is associated with neurodegenerative diseases and the aging process.[19] It also blocks a number of other receptors including α-adrenergic, 5-HT2C, 5-HT5A, and 5-HT6.[20] It is of significance to note that latrepirdine lacks any anticholinergic effects.[21]

See also

References

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Acetylcholinesterases
Ampakines
CX-516 • CX-546 • CX-614 • CX-691 • CX-717 • IDRA-21 • LY-404,187 • LY-503,430 • PEPA • Sunifiram • Unifiram
D1 Agonists
Eugeroics
GABAA α5 Inverse Agonists
H3 Antagonists
mACh Agonists
nACh Agonists
Racetams
Others
Anticholinesterases
Others
Bifemelane • Bilobalide (Ginkgo Biloba) • Ensaculin • Latrepirdine • Lecozotan • Leteprinim • Memantine • Semagacestat

M: PSO/PSI

dsrd (o, p, m, p, a, d, s), sysi/epon, spvo

proc, drug(N5A/5B/5C/6A/6B/6D)

Classes
Antidepressants
7-OH-Amoxapine • Amezepine • Amineptine • Amitriptyline • Amitriptylinoxide • Amoxapine • Aptazapine • Azepindole • Azipramine • Butriptyline • Cianopramine • Ciclazindol • Ciclopramine • Clomipramine • Cotriptyline • Cyanodothiepin • Demexiptiline • Depramine/Balipramine • Desipramine • Dibenzepine • Dimetacrine • Dosulepin/Dothiepin • Doxepin • Enprazepine • Esmirtazapine • Fluotracen • Hepzidine • Homopipramol • Imipramine • Imipraminoxide • Intriptyline • Iprindole • Ketipramine • Litracen • Lofepramine • Losindole • Loxapine • Maprotiline • Mariptiline • Mazindol • Melitracen • Metapramine • Mezepine • Mianserin • Mirtazapine • Naranol • Nitroxazepine • Nortriptyline • Noxiptiline • Octriptyline • Opipramol • Oxaprotiline • Pipofezine • Pirandamine • Propizepine • Protriptyline • Quinupramine • Setiptiline/Teciptiline • Tandamine • Tampramine • Tianeptine • Tienopramine • Trimipramine
Antihistamines
Antipsychotics
Acetophenazine • Amoxapine • Asenapine • Butaclamol • Butaperazine • Carphenazine • Carpipramine • Chlorpromazine • Chlorprothixene • Ciclindole • Clocapramine • Clomacran • Clotiapine • Clozapine • Flucindole • Fluotracen • Flupentixol • Fluphenazine • Gevotroline • Homopipramol • Levomepromazine/Methotrimeprazine • Loxapine • Maroxepin • Mesoridazine • Metitepine/Methiothepin • Metoxepin • Mosapramine • Naranol • Olanzapine • Perazine • Perphenazine • Periciazine • Piperacetazine • Pipotiazine • Piquindone • Prochlorperazine • Promazine • Prothipendyl • Quetiapine • Sulforidazine • Thiethylperazine • Thiopropazate • Thioridazine • Thiothixene • Trifluoperazine • Triflupromazine • Zotepine • Zuclopenthixol
Others
de:Latrepirdin ru:Димебон
  1. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  2. ↑ Shevtsova EF, Kireeva EG, Bachurin SO (2005). "Mitochondria as the target for neuroprotectors". Vestnik Rossiiskoi Akademii Meditsinskikh Nauk (in Russian) (9): 13–17. PMID 16250325. 
  3. ↑ 3.0 3.1 Novel Alzheimer's Drug Flops, MedPage Today, March 03, 2010
  4. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  5. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  6. ↑ Pollack, Andrew (2007-06-11). "Antihistamine Shows Promise in Treating Alzheimer's". New York Times. Retrieved 2010-05-01. 
  7. ↑ Phend Crystal, Jasmer Robert (2008-07-17). "Old Antihistamine Pops Up as Potential Alzheimer's Therapy". Medpage Today. 
  8. ↑ Doody Rachelle S; et al. (2008-07-19). "Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: A randomised, double-blind, placebo-controlled study". Lancet. 372 (9634): 207–215. doi:10.1016/S0140-6736(08)61074-0. PMID 18640457. 
  9. ↑ http://www.reuters.com/article/pressRelease/idUS117499+15-Apr-2009+PRN20090415 "Pfizer and Medivation Initiate Phase 3 Trial of Dimebon Added to Donepezil in Patients with Alzheimer's Disease" Apr 2009
  10. ↑ http://clinicaltrials.gov/ct2/show/NCT00838110 "A Phase 3 Study To Evaluate The Safety And Tolerability Of Dimebon Patients With Mild To Moderate Alzheimer's Disease"
  11. ↑ http://clinicaltrials.gov/ct2/show/NCT00912288 "A Phase 3 Efficacy Study Of Dimebon In Patients With Moderate To Severe Alzheimer's Disease"
  12. ↑ http://clinicaltrials.gov/ct2/show/NCT00939783 "An Extension To The B1451027 Protocol To Evaluate The Long Term Safety And Tolerability Of Dimebon In Patients With Alzheimer's Disease"
  13. ↑ http://clinicaltrials.gov/ct2/show/NCT00954590 "A Safety and Efficacy Study Evaluating Dimebon (Latrepirdine) in Patients With Moderate to Severe Alzheimer's Disease (CONTACT)"
  14. ↑ "Pfizer And Medivation Initiate Phase 3 Trial Of Dimebon In Patients With Huntington Disease" (Press release). Pfizer Inc.. 2009-07-30. http://newsblaze.com/story/2009073005345800002.bw/topstory.html. Retrieved July 31, 2009. 
  15. ↑ Dimebon Disappoints in Phase 3 Trial
  16. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  17. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  18. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  19. ↑ "Medivation's Dimebon(TM) Maintains Statistically Significant Benefit on All Five Efficacy Endpoints in Alzheimer's Disease Trial After One Year of Therapy" (Press release). 2007-06-11. http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/06-11-2007/0004605280&EDATE=. 
  20. ↑ Wu J, Li Q, Bezprozvanny I (2008). "Evaluation of Dimebon in cellular model of Huntington's disease". Molecular Neurodegeneration. 3: 15. doi:10.1186/1750-1326-3-15. PMC 2577671 Freely accessible. PMID 18939977. 
  21. ↑ Gankina EM, Porodenko NV, Kondratenko TI, Severin ES, Kaminka ME, Mashkovskiĭ MD (1993). "[The effect of antihistaminic preparations on the binding of labelled mepyramine, ketanserin and quinuclidinyl benzilate in the rat brain]". Eksperimental'naia I Klinicheskaia Farmakologiia (in Russian). 56 (1): 22–4. PMID 8100727. 
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