Pyrazole-5-carboxamides, novel inhibitors of receptor for advanced glycation end products (RAGE)

• Design, synthesis and SAR analysis of novel pyrazole-5-carboxamides as improved RAGE inhibitor are described.
• SPR study and analyses of the molecular docking well support the improved RAGE inhibition by pyrazole-5-carboxamides.
• In vivo effects and solubility of the identified RAGE inhibitors are also discussed.

In an effort to develop novel inhibitors of receptor for advanced glycation end products (RAGE) for the treatment of Alzheimer's disease, a series of pyrazole-5-carboxamides were designed, synthesized and biologically evaluated. Analyses of the extensive structure–activity relationship (SAR) led us to identify a 4-fluorophenoxy analog (40) that exhibited improved in vitro RAGE inhibitory activity and more favorable aqueous solubility than the parent 2-aminopyrimidine, 1. Surface plasmon resonance (SPR) and molecular docking study strongly supported the RAGE inhibitory activity of pyrazole-5-carboxamides. The brain Aβ-lowering effect of 40 is also described.

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