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- W2000940358 abstract "The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin supergene family that can bind to a range of functionally and structurally diverse ligands. The amyloid beta (Aβ) peptides 1–40 and 1–42 are key ligands implicated in the pathology of neurodegenerative Alzheimer's disease and bind to RAGE with nanomolar affinity. Furthermore, RAGE expression is upregulated in Alzheimer's brains compared with age-matched controls. Using Translational Technology™, we have discovered small molecules that inhibit the binding of Aβ peptides to RAGE. Here we report preclinical data on the mechanisms of these small-molecule inhibitors to further characterize the role of RAGE in the pathophysiology of Alzheimer's disease. Other effects of the small-molecule inhibitors include preventing interaction of RAGE with additional RAGE ligands including S100B, HMGB1, and CML, indicating a common binding site for these ligands on RAGE. We have also demonstrated inhibition of ligand-mediated signaling in different RAGE-expressing human cell types, for example, the RAGE ligand-mediated release of cytokines from the human monocytic cell line THP-1 was attenuated by small-molecule ligands at potencies similar to the in-vitro assays. Neurotoxicity caused by treating SH-SY5Y neuroblastoma cells with micromolar concentrations of Aβ peptide was also blocked by these small molecules. PF-04494700 (formerly TTP488) is the most advanced small-molecule RAGE antagonist in development and has demonstrated efficacy in two peripheral models of inflammation, delayed type hypersensitivity, and splenic amyloid formation. Moreover, PF-04494700 achieved high brain exposure and, when dosed chronically, strongly attenuated Aβ deposition and cognitive deficits in a transgenic Aβ-depositing mouse model. These data confirm and extend previous reports implicating RAGE in the pathogenesis of Alzheimer's disease and indicate that small-molecule RAGE antagonists are a viable therapeutic avenue for Alzheimer's disease." @default.
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- W2000940358 date "2008-07-01" @default.
- W2000940358 modified "2023-09-27" @default.
- W2000940358 title "P2-374: Small-molecule inhibitors of the receptor for advanced glycation end products (RAGE) are an effective therapy in animal models of Alzheimer's disease" @default.
- W2000940358 doi "https://doi.org/10.1016/j.jalz.2008.05.1452" @default.
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