O. P. Goel, R. Dembinski
May 4, 2015
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Organic Preparations and Procedures International
Abstract
Latrepirdine, also known as dimebolin and commercialized in the form of a dihydrochloride salt as dimebon (10), is an antihistamine drug used clinically in Russia since 1983. Dimebon is a non-selective antihistamine that displays cognitive enhancing abilities and does not inhibit acetylcholinesterase activity. It exhibits neuroprotective activity in cellular models of Alzheimer’s and Huntington’s disease and preserves cognitive function following administration to AF64A lesioned rats. It protects neurons against the neurotoxic action of the b-amyloid fragments of amyloid precursor protein (APP). In 2000, the potential use of dimebon in slowing down the progression of mild to mid-stages of Alzheimer’s disease (AD) was suggested by Russian scientists. Numerous clinical studies were initiated in the United States and in 2009, Pfizer and Medivation initiated a phase III trial aiming for FDA approval. However, these clinical trials failed to show benefit from dimebon in the treatment of AD patients. Concurrently, AD research had begun to examine the role of copper in Ab amyloid peptides’ aggregation and toxicity in the brain. Studies have shown that CuC2 and Ab peptides form complexes that induce Ab aggregation and cause cognitive deficits. Furthermore, higher serum copper levels in AD patients compared to cognitively normal individuals support a role for CuC2 in AD pathophysiology. Thus, various drugs including clioquinol and ammonium tetrathiomolybdate (TM) – a potent CuC2 complexing agent used to bind circulating excess CuC2 in patients with Wilson’s disease – have been tested to modulate the amount of CuC2 in AD models. Ammonium tetrathiomolybdate was shown to lower insoluble b-amyloid levels in transgenic mice (Tg2576) over expressing APP. Memantine, antagonist of N-methyl-D-aspartate (NMDA), is widely prescribed to treat AD patients. Goel has described the preparation of memantine tetrathiomolybdate, which is dual-acting by virtue of combining in one molecular entity the neuroprotective NMDA antagonist activity of memantine with the strong copper-complexing properties of thiomolybdate ion. Thus, it was natural to synthesize latrepirdine tetrathiomolybdate for testing in AD models and this required the preparation of dimebon since at the time this research was initiated, it was not commercially available even in small quantities.