SYNTHESIS OF CYCLOPROPYL PEPTIDOMIMETICS AS BACE1 INHIBITORS

Abstract

Alzheimer's disease (AD) affects over 4.5 million Americans and due to its widespread social and economic impact, development of a drug to slow down or halt progression is imperative. AD is a form of late-life mental deficiency marked by progressive memory and cognitive impairment. Abnormal accumulation of amyloid plaques and neurofibrillary tangles are key biomarkers in AD. Amyloid plaques consist of an insoluble secreted amino acid derivative formed through the proteolytic cleavage of the amyloid precursor protein (APP) by two distinct proteases: β-, and γ-secretase. Much research has been focused on the design and development of a β-secretase (BACE) inhibitor, since animal models have shown repeatedly inhibition of BACE decreases amyloid plaque formation. Peptidomimetics, the mimicking of natural peptide structure, as a means for drug design, was used as an approach to synthesize a series of leucine cyclopropane-derived BACE inhibitors. The synthetic route included nitrocyclopropanation and a transfer hydrogenation as key steps to produce the core structure. Attempts were made to couple the terminal amine of the core to a side chain common to known BACE inhibitors.