From bitopic inhibitors to multitarget drugs for the future treatment of Alzheimer’s disease

34 p.-17 fig.Dementia is one of the main causes of disease burden for developed regions. According to the World Health Organization (WHO), these diseases will become the world’s second leading cause of death by the middle of the century, overtaking cancer. This will have a dramatic impact in medical care, as well as important social and economic implications, unless more effective preventive procedures or treatments become available. Alzheimer’s disease (AD) is the most common cause of dementia, accounting for probably 50-75% of all dementias worldwide, followed by vascular dementia, mixed dementia, and Lewy body dementia. Currently, drugs being used to treat AD are AChE inhibitors such as donepezil, rivastigmine and galantamine, for mild to moderate stages. Alternative therapy in its severe stage is memantine, an antagonist of the NMDA-subtype glutamate receptors. However, these drugs only provides temporary benefits by improving symptoms, but do not alter disease progression, except temporarily, in some patients. During the past years different approaches have been developed to provide a more efficient treatment for AD. In addition to the discovery of emerging targets and new drugs aiming at a single target, given the complexity of the disease different targets should be engaged simultaneously. Strategies have explored bitopic inhibitors- acting on different sites of the acetylcholinesterase enzyme producing at least two different activities- to multi-target drugs-acting on different therapeutic targets. In this review, we explore the journey from bitopic inhibitor strategy to multi-target drugs for future AD treatment.Peer reviewe