Chemistry:Latrepirdine

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Short description: Antihistamine drug
Latrepirdine
Dimebolin.svg
Clinical data
Trade namesDimebon
Routes of
administration		Oral
ATC code
  • None
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
Chemical and physical data
FormulaC21H25N3
Molar mass319.452 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]

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]

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.[17]

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

See also

References

  1. ↑ "[Action of dimebon on histamine receptors]" (in ru). Farmakologiia I Toksikologiia 46 (4): 27–29. July–August 1983. PMID 6225678. 
  2. ↑ "[Mitochondria as the target for neuroprotectors]" (in ru). Vestnik Rossiiskoi Akademii Meditsinskikh Nauk (9): 13–17. 2005. PMID 16250325. 
  3. ↑ 3.0 3.1 3.2 Novel Alzheimer's Drug Flops, MedPage Today, March 03, 2010
  4. ↑ 4.0 4.1 "Phase III CONCERT Trial of Latrepirdine. Negative results.". Pharmaceutical Medicine 26 (2): 113–115. 2012. doi:10.1007/BF03256900. 
  5. ↑ 5.0 5.1 5.2 "Phase III Failure Leads Medivation and Pfizer to Ditch Dimebon for Huntington Disease - GEN". 2011-04-12. http://www.genengnews.com/gen-news-highlights/phase-iii-failure-leads-medivation-and-pfizer-to-ditch-dimebon-for-huntington-disease/81244981/. 
  6. ↑ "Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer". Annals of the New York Academy of Sciences 939 (1): 425–435. June 2001. doi:10.1111/j.1749-6632.2001.tb03654.x. PMID 11462798. Bibcode: 2001NYASA.939..425B. 
  7. ↑ "Dimebon improves learning in animals with experimental Alzheimer's disease". Bulletin of Experimental Biology and Medicine 129 (6): 544–546. June 2000. doi:10.1007/BF02434871. PMID 11022244. 
  8. ↑ "Antihistamine Shows Promise in Treating Alzheimer's". The New York Times. 2007-06-11. https://www.nytimes.com/2007/06/11/business/11drug.html?ei=5090&en=6dd260f0ecf61466&ex=1339214400&partner=rssuserland&emc=rss&pagewanted=print. 
  9. ↑ "Old Antihistamine Pops Up as Potential Alzheimer's Therapy". MedPage Today. 2008-07-17. http://www.medpagetoday.com/Geriatrics/AlzheimersDisease/tb/10174. 
  10. ↑ "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. July 2008. doi:10.1016/S0140-6736(08)61074-0. PMID 18640457. 
  11. ↑ "Pfizer and Medivation Initiate Phase 3 Trial of Dimebon Added to Donepezil in Patients with Alzheimer's Disease". Reuters. April 2009. https://archive.today/20130201080708/http://www.reuters.com/article/pressRelease/idUS117499+15-Apr-2009+PRN20090415. 
  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". http://www.alzforum.org/new/detail.asp?id=2387. 
  17. ↑ "Latrepirdine for Alzheimer's disease". The Cochrane Database of Systematic Reviews 2015 (4): CD009524. April 2015. doi:10.1002/14651858.CD009524.pub2. PMID 25897825. 
  18. ↑ "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. November 2001. doi:10.1023/A:1017972709652. PMID 11865327. 
  19. ↑ "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. November 2003. doi:10.1023/B:BEBM.0000017097.75818.14. PMID 14968164. 
  20. ↑ "Mitochondria as a target for neurotoxins and neuroprotective agents". Annals of the New York Academy of Sciences 993 (1): 334–44; discussion 345–9. May 2003. doi:10.1111/j.1749-6632.2003.tb07541.x. PMID 12853325. Bibcode: 2003NYASA.993..334B. 
  21. ↑ "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.
  22. ↑ "Evaluation of Dimebon in cellular model of Huntington's disease". Molecular Neurodegeneration 3: 15. October 2008. doi:10.1186/1750-1326-3-15. PMID 18939977. 
  23. ↑ "[The effect of antihistaminic preparations on the binding of labelled mepyramine, ketanserin and quinuclidinyl benzilate in the rat brain]" (in ru). Eksperimental'naia i Klinicheskaia Farmakologiia 56 (1): 22–24. 1993. PMID 8100727. 



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