hybrid molecule combining acetylcholinesterase inhibitor and NMDA receptor antagonist
Mode of action:
- acetylcholinesterase inhibition
- N-methyl-D-aspartate (NMDA) receptor antagonism
University Hospital Hradec Kralove, Czech Republic
Currently, despite a robust effort is being made to elucidate the underlying mechanisms of Alzheimer’s disease together with the fact that transitioning of these findings into new therapeutic approaches is still being a challenge, cholinesterase inhibitors and memantine still remain the only approved drugs for treatment of AD symptoms. Tacrine promoting an increase in the concentration and duration of action of synaptic acetylcholine thus causing an enhancement of cholinergic neurotransmission, was the first approved drug for treatment of cognitive symptoms of AD. In spite of dose limiting side effects it displayed strong cognitive stimulation. Therefore, over the past two decades, a great deal of synthetic efforts has been expended to find tacrine derivatives with improved pharmacological properties. Thus, 6-chlorotacrine represents a derivative with more favorable inhibitory effect on acetylcholinesterase as compared to its parent compound. Memantine proved to be an efficacious treatment for patients with dementia of Alzheimer’s type. It is safe and well-tolerated in the elderly patients. The combination therapy of acetylcholinesterase (AChE) inhibitors with memantine has already been approved with more positive outcomes than administration of each compound separately. Thus, we presume that combination of NMDA receptor antagonist memantine with AChE inhibitor in one molecule could bring more benefit rather than using single entities separately in one pill possibly due to a better pharmacokinetic and pharmacodynamics profile.
|Discovery||Lead-ident.||Lead-optim.||Preclinics||Phase 1||Phase 2||Phase 3|