Alzheimer's disease (AD) is well known as one of the most common neurodegenerative disease in elderly individuals. According to �b-amyloid (Ab) hypothesis�, Ab peptide is central to the pathological cascade involved in the pathogenesis of AD. Ab is produced mostly in somatic cells through the proteolysis of amyloid precursor protein (APP), and the entry of Ab into the brain and subsequent accumulation is essential for the pathogenesis of AD. Receptor for advanced glycation end products (RAGE)-Ab interaction not only promotes the transport of Ab into the brain, but also activates NF-kB, a transcription factor that plays a crucial role in various inflammatory responses. In this context, the inhibition of the RAGE-Ab interaction has been recognized as more preclusive and curative AD treatment strategy.In connection with the development of novel RAGE inhibitors as potential AD therapeutics, we designed and synthesized on the structural basis of a monomeric advance glycation end product (AGE). Subsequently, we identified a novel scaffold for RAGE-inhibitory activity. We also established the structure-activity relationship of the inhibitors based on the in vitro RAGE inhibition. In particular, one of the analogs resulted in the significant inhibition of Ab accumulation in the brain and in a noticeable improvement in cognitive function in AD model mice after oral administration. The mechanism of the RAGE inhibitory activities was partly elucidated by SPR analysis, the results of which supported the hypothesis that the direct binding of the inhibitorwith RAGE contributed to its RAGE-inhibitory activities. In addition, the binding mode of the inhibitors with RAGE was predicted by a docking study of the inhibitors on the RAGE V-domain.

Ligand-based design, synthesis, and biological evaluation of a novel series of RAGE (Receptor for Advanced Glycation End Products) inhibitors

245th National Meeting (2013)

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