6-Phenoxy-2-phenylbenzoxazoles, novel inhibitors of receptor for advanced glycation end products (RAGE)

Receptor for advanced glycation end products (RAGE) is known to be involved in the transportation of amyloid beta (A beta) peptides and causes the accumulation of Ab in the brain. Moreover, recent studies suggest that the interactions between RAGE and Ab peptides may be the culprit behind Alzheimer's disease (AD). Inhibitors of the RAGE-A beta interactions would not only prevent the accumulation of toxic Ab in the brain, and but also block the progress of AD, therefore, have the potential to provide a 'disease-modifying therapy'. In this study, we have developed a series of 6-phenoxy-2-phenylbenzoxazole analogs as novel inhibitors of RAGE. Among these derivatives, we found several effective inhibitors that block the RAGE-Ab interactions without causing significant cellular toxicity. Further testing showed that compound 48 suppressed Ab induced toxicity in mouse hippocampal neuronal cells and reduced Ab levels in the brains of a-transgenic mouse model of AD after oral administration. (C) 2015 Elsevier Ltd. All rights reserved.