Latrepirdine

Last updated
Latrepirdine
Dimebolin.svg
Clinical data
Trade names Dimebon
Routes of
administration 		Oral
ATC code
  • None
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
  • 2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-1H-pyrido(4,3-b)indole
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard 100.119.053 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H25N3
Molar mass 319.452 g·mol−1

Latrepirdine (INN, also known as dimebolin and sold as Dimebon) is an antihistamine drug which has been used clinically in Russia since 1983. [1]

Contents

Research was conducted in both Russia and western nations into potential applications as a neuroprotective drug to treat Alzheimer's disease and, possibly, as a nootropic, as well. [2] After a major phase III clinical trial for Alzheimer's disease (AD) treatment failed to show any benefit, three other AD trials continued. [3] Major industry-based development in this indication essentially stopped after another Phase III trial suffered the same fate in 2012. [4] Latrepirdine failed in the phase III trial for Huntington disease. [5]

Uses

Latrepirdine is an orally active, small molecule compound that has been shown to inhibit brain cell death in animal models of Alzheimer's disease and Huntington's disease. Research suggests it may also have cognition-enhancing effects in healthy individuals, in the absence of neurodegenerative disease pathology. [6] However, because of negative results in human clinical trials, the drug remains unlicensed for any neurodegenerative condition. [3] [5]

Clinical trials

Alzheimer's disease

Latrepirdine attracted renewed interest in 2009 after being shown in small preclinical trials 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. [7] Preliminary results from human trials have also been promising. In an initial six-month phase II trial, results have shown significant improvement over placebo at 12 months. [8] Latrepirdine showed promising results in a phase III-equivalent, double-blind trial in Russia with mild–moderate stage patients. [9] [10] In April 2009, Pfizer and Medivation initiated a phase III trial (CONCERT study) aiming for FDA approval. [11] 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. [12] [13] [14] [15]

In July 2009, Pfizer and Medivation announced that "latrepirdine" was to be the proposed international nonproprietary name for latrepirdine for the treatment of Alzheimer's.[ citation needed ]

In March 2010, the results of a clinical trial phase III were released; the investigational Alzheimer's disease drug dimebon failed in the pivotal CONNECTION trial of patients with mild-to-moderate disease. [16] Pfizer had paid $225 million after bidding against several pharmaceutical companies to purchase the rights to Dimebon. [17]

With CONCERT, the remaining Pfizer and Medivation Phase III trial for latrepirdine in Alzheimer's disease failed in 2012, effectively ending the development in this indication. [4]

A Cochrane meta-analysis of the three pivotal phase III efficacy trials found no significant effect of latrepirdine on cognition and function in mild-to-moderate Alzheimer's patients, though there appears to be a modest benefit for overall behavior disturbances. [18] Latredipine thus failed to alter the existing pharmacologic management of Alzheimer's disease.

Huntington's disease

In April 2011, latrepirdine failed in a phase III clinical trial of patients affected with Huntington's disease. [5] The trial was sponsored by Medivation Inc. and Pfizer.

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, [19] modulating the action of AMPA and NMDA glutamate receptors, [20] and may exert a neuroprotective effect by blocking a novel target that involves mitochondrial pores, [21] which are believed to play a role in the cell death that is associated with neurodegenerative diseases and the aging process. [22] It also blocks a number of other receptors, including α-adrenergic, 5-HT2C, 5-HT5A, and 5-HT6. [23] Notably, latrepirdine lacks any anticholinergic effects. [24]

See also

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References

  1. ↑ Matveeva IA (July–August 1983). "[Action of dimebon on histamine receptors]". Farmakologiia i Toksikologiia (in Russian). 46 (4): 27–29. PMID   6225678.
  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. 1 2 3 Novel Alzheimer's Drug Flops, MedPage Today, March 03, 2010
  4. 1 2 Sweetlove M (2012). "Phase III CONCERT Trial of Latrepirdine. Negative results". Pharmaceutical Medicine. 26 (2): 113–115. doi:10.1007/BF03256900. S2CID   699473.
  5. 1 2 3 "Phase III Failure Leads Medivation and Pfizer to Ditch Dimebon for Huntington Disease - GEN". GEN. 2011-04-12.
  6. ↑ Bachurin S, Bukatina E, Lermontova N, Tkachenko S, Afanasiev A, Grigoriev V, et al. (June 2001). "Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer". Annals of the New York Academy of Sciences. 939 (1): 425–435. Bibcode:2001NYASA.939..425B. doi:10.1111/j.1749-6632.2001.tb03654.x. PMID   11462798. S2CID   31389614.
  7. ↑ Lermontova NN, Lukoyanov NV, Serkova TP, Lukoyanova EA, Bachurin SO (June 2000). "Dimebon improves learning in animals with experimental Alzheimer's disease". Bulletin of Experimental Biology and Medicine. 129 (6): 544–546. doi:10.1007/BF02434871. PMID   11022244. S2CID   32513986.
  8. ↑ Pollack A (2007-06-11). "Antihistamine Shows Promise in Treating Alzheimer's". The New York Times . Retrieved 2010-05-01.
  9. ↑ Crystal P, Robert J (2008-07-17). "Old Antihistamine Pops Up as Potential Alzheimer's Therapy". MedPage Today.
  10. ↑ Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, et al. (July 2008). "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. S2CID   205951657.
  11. ↑ "Pfizer and Medivation Initiate Phase 3 Trial of Dimebon Added to Donepezil in Patients with Alzheimer's Disease". Reuters. April 2009. Archived from the original on 2013-02-01. Retrieved 2009-07-22.{{cite web}}: CS1 maint: bot: original URL status unknown (link)
  12. ↑ Clinical trial number NCT00838110 for "A Phase 3 Study To Evaluate The Safety And Tolerability Of Dimebon Patients With Mild To Moderate Alzheimer's Disease" at ClinicalTrials.gov
  13. ↑ Clinical trial number NCT00912288 for "A Phase 3 Efficacy Study Of Dimebon In Patients With Moderate To Severe Alzheimer's Disease" at ClinicalTrials.gov
  14. ↑ Clinical trial number NCT00939783 for "An Extension To The B1451027 Protocol To Evaluate The Long Term Safety And Tolerability Of Dimebon In Patients With Alzheimer's Disease" at ClinicalTrials.gov
  15. ↑ Clinical trial number NCT00954590 for "A Safety and Efficacy Study Evaluating Dimebon (Latrepirdine) in Patients With Moderate to Severe Alzheimer's Disease (CONTACT)" at ClinicalTrials.gov
  16. ↑ "Dimebon Disappoints in Phase 3 Trial - ALZFORUM". www.alzforum.org.
  17. ↑ Miller, G (2010). "The Puzzling Rise and Fall of a Dark-Horse Alzheimer's Drug". Science. 327 (5971): 1309. doi:10.1126/science.327.5971.1309. PMID   20223954.
  18. ↑ Chau S, Herrmann N, Ruthirakuhan MT, Chen JJ, Lanctôt KL (April 2015). "Latrepirdine for Alzheimer's disease". The Cochrane Database of Systematic Reviews. 2015 (4): CD009524. doi:10.1002/14651858.CD009524.pub2. PMC   7388906 . PMID   25897825.
  19. ↑ Lermontova NN, Redkozubov AE, Shevtsova EF, Serkova TP, Kireeva EG, Bachurin SO (November 2001). "Dimebon and tacrine inhibit neurotoxic action of beta-amyloid in culture and block L-type Ca(2+) channels". Bulletin of Experimental Biology and Medicine. 132 (5): 1079–1083. doi:10.1023/A:1017972709652. PMID   11865327. S2CID   822340.
  20. ↑ Grigorev VV, Dranyi OA, Bachurin SO (November 2003). "Comparative study of action mechanisms of dimebon and memantine on AMPA- and NMDA-subtypes glutamate receptors in rat cerebral neurons". Bulletin of Experimental Biology and Medicine. 136 (5): 474–477. doi:10.1023/B:BEBM.0000017097.75818.14. PMID   14968164. S2CID   13207412.
  21. ↑ Bachurin SO, Shevtsova EP, Kireeva EG, Oxenkrug GF, Sablin SO (May 2003). "Mitochondria as a target for neurotoxins and neuroprotective agents". Annals of the New York Academy of Sciences. 993 (1): 334–44, discussion 345–9. Bibcode:2003NYASA.993..334B. doi:10.1111/j.1749-6632.2003.tb07541.x. PMID   12853325. S2CID   15818833.
  22. ↑ "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. Archived from the original on 2012-08-06. Retrieved 2020-02-23.
  23. ↑ Wu J, Li Q, Bezprozvanny I (October 2008). "Evaluation of Dimebon in cellular model of Huntington's disease". Molecular Neurodegeneration. 3: 15. doi: 10.1186/1750-1326-3-15 . PMC   2577671 . PMID   18939977.
  24. ↑ 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): 22–24. PMID   8100727.
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