Synonyms: Dimebolin, Latrepirdine, Pf-01913539
Chemical Name: 3,6-dimethyl-9-(2-methyl-pyridyl-5)-ethyl-1,2,3,4-tetrahydro-γ-carboline dihydrochloride
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline), Unknown
Condition(s): Alzheimer's Disease, Huntington's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued), Huntington's Disease (Discontinued)
Company: Medivation, Inc.
Approved for: Anti-histamine use in Russia
Dimebon is an antihistamine that has been used in Russia since the 1980s to treat allergic rhinitis.
Dimebon is a pleiotropic drug with activities beyond blocking H1 histamine receptors. A mechanism of action for cognitive benefit has never been conclusively established; however, a broad spectrum of effects on neurologically relevant targets was proposed based on various cell- and animal-based studies. For example, Dimebon has been variously reported to modulate the activity of certain channels and neurotransmitter systems, including L-type and voltage-gated calcium channels, AMPA and NMDA glutamate receptors, α-adrenergic receptors, and serotonergic or dopaminergic receptors.
Rodent models suggested benefits in avoidance tests in rats and hippocampal learning, though animal-behavior studies overall reported mixed results. Dimebon also has been proposed to be neurogenic, to exert protective effects on neuronal mitochondria, to reduce aggregation of misfolded proteins, to upregulate autophagy, and to be neuroprotective via a variety of pathways including blocking Aβ-mediated toxicity (for reviews, see Bezprozvanny, 2010; Bharadwadj et al., 2013).
Between 2001 and 2010, Dimebon was repurposed for the treatment of Alzheimer's and Huntington's and underwent clinical evaluation for cognitive and psychiatric benefit in those diseases. Phase 1 and 2 trials of a total of 197 Alzheimer's patients in Russia were followed by two Phase 3 trials in some 1,600 patients with mild to moderate AD conducted in the Americas, Europe, Australia, and New Zealand. The Phase 2 trial reported significant improvement over placebo, but neither Phase 3 study detected change in any primary or secondary outcome (Bachurin et al., 2001; Doody et al., 2008; Mar 2010 news story).
Likewise in Huntington's, a Phase 2 study reported significant improvement on cognitive measures, but a subsequent Phase 3 trial in 403 patients was negative on all outcomes (Horizon Investigators, 2013). A peer-reviewed meta-analysis of all Dimebon trials later confirmed that the drug had no significant benefit on cognition (Cano-Cuenca et al., 2014).
For detailed news chronicling Dimebon's development history, see Jan 2012 news story; Apr 2011 news story; Apr 2010 news story; Mar 2010 news story; Oct 2009 news story; Aug 2008 news story; May 2007 news story; and all news on Dimebon.
- Dimebon Disappoints in Phase 3 Trial
- CONCERT Trial of Dimebon Falls Flat
- No Effect Seen in Huntington’s Disease Trial of Dimebon
- Research Brief: Medivation Scales Back
- Dimebon: Bright Star or Black Hole?
- Chicago: Dimebon Safe for 18 Months
- Boston: Clinical Trial Results for Dimebon Unveiled
- Bachurin S, Bukatina E, Lermontova N, Tkachenko S, Afanasiev A, Grigoriev V, Grigorieva I, Ivanov Y, Sablin S, Zefirov N. Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer. Ann N Y Acad Sci. 2001 Jun;939:425-35. PubMed.
- Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D, . 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. 2008 Jul 19;372(9634):207-15. PubMed.
- A Randomized, Double-blind, Placebo-Controlled Study of Latrepirdine in Patients With Mild to Moderate Huntington Disease. Arch Neurol. 2012 Oct 1;:1-9. PubMed.
- Cano-Cuenca N, Solís-García Del Pozo JE, Jordán J. Evidence for the Efficacy of Latrepirdine (Dimebon) Treatment for Improvement of Cognitive Function: A Meta-Analysis. J Alzheimers Dis. 2014 Jan 1;38(1):155-64. PubMed.
- Bezprozvanny I. The rise and fall of Dimebon. Drug News Perspect. 2010 Oct;23(8):518-23. PubMed.
- Bharadwaj PR, Bates KA, Porter T, Teimouri E, Perry G, Steele JW, Gandy S, Groth D, Martins RN, Verdile G. Latrepirdine: molecular mechanisms underlying potential therapeutic roles in Alzheimer's and other neurodegenerative diseases. Transl Psychiatry. 2013 Dec 3;3:e332. PubMed.
- Egea J, Romero A, Parada E, León R, Dal-Cim T, López MG. Neuroprotective effect of dimebon against ischemic neuronal damage. Neuroscience. 2014 May 16;267:11-21. Epub 2014 Mar 4 PubMed.
- Rosini M, Simoni E, Bartolini M, Soriano E, Marco-Contelles J, Andrisano V, Monti B, Windisch M, Hutter-Paier B, McClymont DW, Mellor IR, Bolognesi ML. The Bivalent Ligand Approach as a Tool for Improving the in vitro Anti-Alzheimer Multitarget Profile of Dimebon. ChemMedChem. 2013 Aug;8(8):1276-81. PubMed.
- Steele JW, Gandy S. Latrepirdine (Dimebon®), a potential Alzheimer therapeutic, regulates autophagy and neuropathology in an Alzheimer mouse model. Autophagy. 2013 Apr;9(4):617-8. PubMed.
- Hopkins CR. ACS chemical neuroscience molecule spotlight on dimebon. ACS Chem Neurosci. 2010 Sep 15;1(9):587-8. PubMed.
- Sachdeva D, Burns A. Dimebolin in dementia. CNS Neurosci Ther. 2011 Jun;17(3):199-205. PubMed.