Design, Synthesis and Biological Evaluation of Novel Receptor for Advanced Glycation End-product (RAGE) Inhibitor

Abstract

Alzheimers disease (AD) is the most common progressive dementia and a chronic neurodegenerative disorder that leads to progressive disturbances of cognitive functions. Although Abetais produced from almost all cells in the body by proteolysis of APP, the process of Abeta accumulation into brain is required for pathogenesis of AD. RAGE at BBB is predominantly responsible for plasma-derived soluble Abeta influx into the brain. In Alzheimers disease, RAGE-Abeta interaction dose not only promote the Abeta transport into brain, but also activate nuclear factor-kB (NF-kB). In this context, the AD treatment strategy employing an inhibition of the RAGE-Abeta interaction, which results in restraining deposition of Abeta and the inflammatory response to Abeta in brain, has been expected to be more preclusive and curative. In connection with development of novel RAGE inhibitors for potential AD therapeutics, a series of 2-aminopyrimidines was designed and synthesized on the structural basis of argpyrimidine, one of monomeric AGE at the first. Subsequently, the 4,6-disubstituted 2-aminopyrimidine core was identified as an active novel scaffold for the RAGE-inhibitory activities. Based on this study, potent pyrazole-5-carboxamide core was also identified by heterocycle core modification strategy. The structure-activity relationships of the each series of the scaffolds were also established based on the in vitro RAGE inhibition assay. In particular, the bis(4-chlorophenyl)pyrimidine analog exhibited a significant inhibition of the Abeta (especially toxic soluble Abeta) accumulation in brain and a noticeable improvement in a cognitive function in AD model mice after oral administration. The mode of the RAGE inhibitory activities of the 2-aminopyrimidine analogs was partly elucidated by SPR study, which supported that the direct binding of the inhibitor to RAGE contributed to its RAGE-inhibitory activities. In addition, the binding modes of the inhibitors were predicted by docking study of the inhibitors on the RAGE V-domain.