The rise and fall of Dimebon.

Dimebon (latrepirdine) was developed and used in Russia as an over-the-counter oral antihistamine for allergy treatment. In the early 1990s, Dimebon was characterized as a low-affinity NMDA receptor antagonist by Dr. Sergey Bachurin and his colleagues. An initial small-scale, open-label trial of Dimebon in 14 Alzheimer's disease (AD) patients demonstrated potential efficacy. Dimebon was then patented for the treatment of neurodegenerative disorders and licensed by Medivation. Extremely promising results were obtained in a double-blind, placebo-controlled, phase II AD trial in 183 patients; however, a phase II trial of Dimebon in 91 Huntington's disease patients was much less successful. Recently, a phase III AD trial of Dimebon in 598 patients failed to result in any significant improvement in primary or secondary outcomes. The failure of Dimebon may be in large part due to insufficient understanding of its mechanism of action. The NMDA receptor blocking activity of Dimebon is too weak to be physiologically relevant, while the proposed "novel mitochondrial mechanism of action" lacks credible scientific evidence or a molecular target. Independent studies indicate that the clinical effects of Dimebon most likely result from inhibition of histamine H₁ and serotonin 5-HT₆ receptors. Careful preclinical studies of novel potential therapies are needed to minimize chances of making similar costly mistakes in the future.

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[3]  D. Holtzman,et al.  Acute dosing of latrepirdine (Dimebon™), a possible Alzheimer therapeutic, elevates extracellular amyloid-β levels in vitro and in vivo , 2009, Molecular Neurodegeneration.

[4]  Michael J Marino,et al.  Dimebolin is a 5-HT6 antagonist with acute cognition enhancing activities. , 2009, Biochemical pharmacology.

[5]  R. Doody.  Dimebon as a Potential Therapy for Alzheimer's Disease , 2009, CNS Spectrums.

[6]  M. Goedert,et al.  Methylene blue and dimebon inhibit aggregation of TDP‐43 in cellular models , 2009, FEBS letters.

[7]  J. Marsh,et al.  Animal Models of Polyglutamine Diseases and Therapeutic Approaches* , 2009, Journal of Biological Chemistry.

[8]  I. Bezprozvanny,et al.  Evaluation of Dimebon in cellular model of Huntington's disease , 2008, Molecular Neurodegeneration.

[9]  M. Sano,et al.  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 , 2008, The Lancet.

[10]  Neil Upton,et al.  5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer’s disease , 2008, Neurotherapeutics.

[11]  S. O. Bachurin,et al.  Comparative Study of Action Mechanisms of Dimebon and Memantine on AMPA- and NMDA-Subtypes Glutamate Receptors in Rat Cerebral Neurons , 2003, Bulletin of Experimental Biology and Medicine.

[12]  G. Oxenkrug,et al.  Mitochondria as a Target for Neurotoxins and Neuroprotective Agents , 2003, Annals of the New York Academy of Sciences.

[13]  S. Bachurin,et al.  Dimebon and Tacrine Inhibit Neurotoxic Action of β-Amyloid in Culture and Block L-type Ca2+ Channels , 2001, Bulletin of Experimental Biology and Medicine.

[14]  S. Bachurin,et al.  Antihistamine Agent Dimebon As a Novel Neuroprotector and a Cognition Enhancer , 2001, Annals of the New York Academy of Sciences.

[15]  S. Bachurin,et al.  Dimebon improves learning in animals with experimental Alzheimer's disease , 2000, Bulletin of Experimental Biology and Medicine.

[16]  I. A. Matveeva.  [Action of dimebon on histamine receptors]. , 1983, Farmakologiia i toksikologiia.