PHARMACOLOGICAL EVALUATION OF NOVEL INSULIN-DEGRADING ENZYME INHIBITORS IN ALZHEIMER’S DISEASE MANAGEMENT

BACKGROUND: Alzheimer disease (AD) is a neurodegenerative disease impacting more than 55 million people worldwide and is the most common form of the disorder that is characterized by a progressive decline in cognitive functions, amyloid-b (Ab) plaque formation, neurofibrillary tangles, and neuronal loss. Present forms of therapeutic interventions are rather symptomatic, but not disease-modifying. The increased awareness of metabolic dysfunction in the pathogenesis of AD has made insulin-degrading enzyme (IDE), or insulysin, an excellent therapeutic target. IDE has a dual effect on reducing insulin and Ab peptides and may be at the cross-section of regulating metabolism and clearance of amyloid. There is also a relationship between age-related decrease in IDE activity and AD risk, and IDE deficiency increases the amyloid pathology in transgenic mouse models. The complicated interconnection between diabetes and dementia, which is also referred to as type 3 diabetes, further highlights the therapeutic benefits of IDE. OBJECTIVE: This is a detailed review on the potential of new insulin secretase inhibitors, i.e., Molecules 5 and 7, in the treatment of Alzheimer disease. We evaluate their molecular pathways of action, pharmacology, preclinical efficacy, safety, and clinical translation. We will also evaluate their benefits in comparison to the current treatment methods and talk about the future studies in the direction of IDE-targeted therapies. METHODS: PubMed, Scopus and Web of Science databases were used to identify recent developments in IDE inhibition and AD therapeutics and develop a literature review. RESULTS: Novel insulinase inhibitors have profound neuroprotective activity mediated by several mechanisms, such as increased Aβ clearance, insulin signalling, and neuroinflammation. Molecules 5 and 7 are also rather promising with good pharmacokinetic and blood-brain barrier penetration. CONCLUSION: Molecules 5 and 7 and in particular the insulysin inhibitor are the first AD therapeutic in the paradigm shift providing potential disease-modifying mechanisms that take care of both metabolic dysfunction and amyloid pathology. They have favourable pharmacological characteristics, have shown efficacy in preclinical models and have acceptable safety profiles making them promising clinical development candidates. Such a dual-target intervention can offer better clinical response relative to single-pathway intervention, which could slow disease progression and increase the cognitive performance of AD patients.