RS-1259, a dual inhibitor of AChE and SERT for treating Alzheimers disease

The aging population, combined with new and improved treatments for neurodegenerative disorders such as Alzheimer's and Parkinson's disease will lead to an expansion of the already $30 billion neurodegenerative market. The market for Alzheimer's disease (AD) therapy is expected to grow from 16 million patients to 21 million by 2010 in the seven major pharmaceutical markets. Between 2005 and 2010, drugs for treating Alzheimer's disease could achieve sales of well over $2 billion (for a full analysis of this field see our recent feature “Neurodegenerative Disorders: World Markets 2002-2007”).

A major event in the etiology of AD is the loss of cholinergic fibers which results from the build up of neurotoxic Abeta1-42. Consequently, current therapeutic strategies focus on the use of cholinesterase inhibitors to compensate for the loss of cholinergic innervation and the subsequent neurological deficits. More recently evidence has accumulated suggesting that cholinesterase (AChE) inhibitors may modify the course of disease rather than simply acting to limit its symptoms and in particular AChE inhibitors can block Abeta accumulation. Thus the development of AChE inhibitors continues to be a focus for the pharmaceutical industry. The development of new inhibitors with reduced side effects is required and furthermore the identification of therapeutics that simultaneously target monoamine pathways may also be of benefit. The monoamines have been shown to play a role in cognition however perhaps more importantly they are key to the development of behavioral disorders.

AD patients often exhibit several behavioral abnormalities such as irritability, anxiety, and depression; indeed the latter is reported in 40% of patients with dementia. Selective serotonin reuptake (SERT) inhibitors such as sertraline, when used in combination with the AChE inhibitor, donepezil are therefore useful in the treatment of AD become cognitive improvement is improved whilst affective disorders are limited. However the development of a single entity that both inhibits AChE activity and also monoamine neurotransmission is awaited. Researchers at Sankyo have recently addressed this need and in their J Pharmacol Sci paper, Abe et al report the pharmacological properties of RS-1259, a newly synthesized dual inhibitor of AChE and SERT in rodents. This molecules inhibits AchE with an IC50 value of 105nM, only 10-fold less potent than donepezil, and SERT with an IC50 value of 90nM, 2-fold lower than that of fluoxetine. RS-1259 is therefore not only potent but importantly it inhibits these systems with similar potencies. Inhibition was also observed in an ex vivo model and furthermore RS-1259 simultaneously elevated extracellular levels of ACh and 5-HT in the hippocampus of freely moving rats. Perhaps most importantly RS-1259 was as effective as SERT inhibitors in the 5-HTP enhancement test in mice, suggesting an anti-depressant effect could be expected of the compound, and furthermore RS-1259 reversed aged-related cognitive decline in rats at a dose similar to that of donepezil.

This study demonstrates that RS-1259 may have both anti-depressant and memory enhancing properties and may therefore be of use in the treatment of AD. Clinical studies are eagerly awaited and in addition it would be of interest to determine the effect that this molecule has on Abeta1-42 accumulation.

Entry date Monday, November 10, 2003

Adapted from Abe et al, J Pharmacol Sci. 2003 Sep;93(1):95-105.