FPS-ZM1

FPS-ZM1 is a high-affinity and BBB-permeable RAGE inhibitor with a K_i of 25 nM. IC50 & Target:Ki: 25 nM (RAGE)^[1] In Vitro:FPS-ZM1 inhibits Aβ/RAGE binding in CHO cells with approximately 2-fold greater affinity than its parent molecule, FPS2. FPS-ZM1 inhibits binding of other known RAGE ligands to sRAGE, including S100 calcium-binding protein B and amphoterin. FPS-ZM1 is more effective than FPS2 in reducing Aβ40-induced increases inBACE1 mRNA and protein levels and the generation of sAPPβ, an APP cleavage product of BACE1 indicative of BACE1 activity^[1]. In Vivo:FPS-ZM1 is nontoxic to mice and readily crossed the blood-brain barrier. In aged APP^sw/0 mice overexpressing human Aβ-precursor protein, a transgenic mouse model of AD with established Aβ pathology, FPS-ZM1 inhibits RAGE-mediated influx of circulating Aβ40 and Aβ42 into the brain. In brain, FPS-ZM1 binds exclusively to RAGE, which inhibits β-secretase activity and Aβ production and suppresses microglia activation and the neuro-inflammatory response^[1]. FPS-ZM1 treatment reduces the level of Aβ1-40 and Aβ1-42 in AGEs Rats. It Inhibits AGEs-mediated increase of Aβ-metabolism-related proteins and downregulates AGEs-mediated increase of pro-inflammatory cytokines in the hippocampus. FPS-ZM1 up-Regulates anti-oxidant defense system and attenuated AGEs induced memory impairment in AGEs rats^[2].