Recent Advances in Approved, Withdrawn, Experimental and Investigational Drugs in Clinical Trials for Alzheimer’s disease

Alzheimer’s disease (AD) is an irreversible, chronic degenerative disease that slowly destroys memory and thinking skills, and eventually destroys the ability to carry out the simplest of day-to-day routine tasks. This disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. Presence of beta-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) in brains of the affected patients are the distinguishable characteristics of this disease. Currently, no treatment is available to stop or reverse progression of AD, though it may temporarily improve symptoms. There are four USFDA approved drugs which are helpful for symptomatic treatment in AD namely Donepezil, Rivastigmine, Galantamine and Memantine. Memantine functions as an NMDA receptor antagonist, whereas the other three drugs act by inhibiting the acetylcholinesterase enzyme (AChE) resulting in an increase in the levels of acetylcholine (ACh) in the body. In the past decades, many advancements in the current drugs as well as the experimental drugs for AD have been made and these involve structural modifications and mechanistic improvements to increase the capacity of the molecules to cross the blood brain barrier (BBB). Synthesis of 2-acetylphenol-donepezil hybrids is an example of an approach which was adopted based on MultiTarget Directed Ligand (MTDL) strategy. Recently, synthesis of salicylanilide N-alkyl carbamates was carried out and these were observed to possess higher AChE inhibiting capacity than Rivastigmine. Memogain is an inactive prodrug of galantamine which has shown improved effectiveness, fewer side effects and due to its lipophilic nature is said to penetrate the BBB where it gets cleaved into active galantamine. Huperzine A is another highly selective AChE inhibitor and is approved for use only in China though not by USFDA. Tacrine and Huperazine A were combined together to form a hybrid molecule Huprine X, which is said to possess not only potency but also higher selectivity for AChE inhibition alongside anti-Aβ properties.