Latrepirdine

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Latrepirdine
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
Trade names Dimebon
Legal status
  • ℞ (Prescription only)
Routes of
administration
Oral
Identifiers
CAS Number 3613-73-8
ATC code none
PubChem CID: 197033
ChemSpider 170644
UNII OD9237K1Z6 YesY
Chemical data
Formula C21H25N3
Molecular mass 319.443 g/mol

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] Dimebon 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]

Alzheimer's disease: failed in Phase III clinical trials

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.[16]

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.[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]

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

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  3. 3.0 3.1 3.2 Novel Alzheimer's Drug Flops, MedPage Today, March 03, 2010
  4. 4.0 4.1 Sweetlove M: Phase III CONCERT Trial of Latrepirdine. Negative results. Pharm Med 2012;26(2):113-115
  5. 5.0 5.1 5.2 http://www.genengnews.com/gen-news-highlights/phase-iii-failure-leads-medivation-and-pfizer-to-ditch-dimebon-for-huntington-disease/81244981/
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  11. 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
  12. 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"
  13. http://clinicaltrials.gov/ct2/show/NCT00912288 "A Phase 3 Efficacy Study Of Dimebon In Patients With Moderate To Severe Alzheimer's Disease"
  14. 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"
  15. http://clinicaltrials.gov/ct2/show/NCT00954590 "A Safety and Efficacy Study Evaluating Dimebon (Latrepirdine) in Patients With Moderate to Severe Alzheimer's Disease (CONTACT)"
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  17. Dimebon Disappoints in Phase 3 Trial
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