Review of Synthesis, Biological Assay and QSAR Studies of β-Secretase Inhibitors

Alzheimer's disease (AD) is highly complex. While several pathologies characterize this disease, amyloid plaques, composed of the beta-amyloid peptide, are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that beta-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. The BACE-1 enzyme is essential for the generation of beta-amyloid. BACE-1 knockout mice do not produce beta-amyloid and are free from Alzheimer's associated pathologies, including neuronal loss and certain memory deficits. The fact that BACE-1 initiates the formation of beta-amyloid, and the observation that BACE-1 levels are elevated in this disease provide direct and compelling reasons to develop therapies directed at BACE-1 inhibition, thus reducing beta-amyloid and its associated toxicities. In this sense, quantitative structure-activity relationships (QSAR) could play an important role in studying these beta-secretase inhibitors. QSAR models are necessary in order to guide the beta-secretase synthesis. This work is aimed at reviewing different design and synthesis and computational studies for a very large and heterogeneous series of beta-secretase inhibitors. First, we review design, synthesis, and Biological assay of beta-secretase inhibitors. Next, we review 2D QSAR, 3D QSAR, CoMFA, CoMSIA and Docking with different compounds to find out the structural requirements. Next, we review QSAR studies using the method of Linear Discriminant Analysis (LDA) in order to understand the essential structural requirement for receptor binding for beta-secretase inhibitors.