Azeliragon is a receptor for advanced glycation end-products (RAGE) antagonist. Azeliragon blocks binding of RAGE to ligands including AGEs, Aβ, HMGB1 and S100B to inhibit receptor activation. Azeliragon reduces release of pro-inflammatory factors including IL-1, TNF-α and IL-6 by suppressing downstream inflammatory signals such as NF-κB. Azeliragon is useful for studies on Alzheimer's disease, diabetes-associated cognitive impairment, neuroinflammation and tumor RAGE signaling[1-4].
In vitro, treatment of osteoclast precursors/pre-osteoclasts with 100ng/mL Azeliragon for 3 days inhibited RANKL/M-CSF-induced osteoclast differentiation and mature osteoclast formation from bone marrow-derived cells[5]. Treatment of 4175 and 4T1 cells with 1μM Azeliragon for 24-72 hours weakened cell adhesion to extracellular matrix proteins including collagen, laminin and fibronectin, and reduced cell migration and invasion abilities[6]. Pretreatment of SH-SY5Y cells with 100μM Azeliragon for 1 hour followed by treatment with 300μg/mL Advanced glycation end products (AGEs) for 24 hours increased cell viability and maintained neurite structure, decreased intracellular and mitochondrial reactive oxygen species, downregulated RAGE and NOX4 expression, inhibited PERK-eIF2α-ATF4-CHOP signaling, restored Bcl-2/Bax balance, inhibited caspase-9 and caspase-3 activation, and reduced cytochrome c translocation from mitochondria to cytoplasm and DNA fragmentation[7].
In vivo, daily intraperitoneal injection of 100μg/day or 110μg/day Azeliragon to C57BL/6 mice for 28 days reduced osteoclast numbers on vertebral cancellous and femoral cortical bone surfaces, decreased osteoblast-related gene expression in tibia, increased empty lacunae proportion and elevated bone IL-6 and MCP-1 gene expression, and restored gastrocnemius, extensor digitorum longus and quadriceps muscle mass and myogenesis-related gene expression[8]. Oral administration of 10mg/kg Azeliragon in drinking water to ob/ob mice for 15 days reduced total AGE and MG-H1 levels in bladder tissue, decreased collagen strength, and lowered total urine output[9]. Intraperitoneal injection of 20mg Azeliragon to Aβ1-42-induced SD rats for 5 days shortened latency and increased platform quadrant residence time and distance in Morris water maze, reduced NLRP1/NeuN-positive cell numbers, alleviated neuronal Nissl body loss and apoptosis, and decreased caspase-1, IL-1β and IL-18 protein expression and activity[10].
References:[1] Reddy VP, Aryal P, Soni P. RAGE Inhibitors in Neurodegenerative Diseases. Biomedicines. 2023 Apr 9;11(4):1131.
[2] Luque M, Morales-Gallego M, Sanz-Alvarez M, et al. Cancer-associated fibroblast-derived protein S100-A11 influences the response to anti-HER2 therapies in HER2-positive breast cancer. Neoplasia. 2026;78:101318.
[3] Kim EY, Dryer SE, et al. RAGE and aVβ3-integrin are essential for suPAR signaling in podocytes. Biochim Biophys Acta Mol Basis Dis. 2021 Oct 1;1867(10):166186.
[4] Burstein AH, Sabbagh M, Andrews R, et al. Development of Azeliragon, an Oral Small Molecule Antagonist of the Receptor for Advanced Glycation Endproducts, for the Potential Slowing of Loss of Cognition in Mild Alzheimer's Disease. J Prev Alzheimers Dis. 2018;5(2):149-154.
[5] Davis HM, Valdez S, Gomez L, et al. High mobility group box1(HMGB1) protein regulates osteoclastogenesis through direct actions on osteocytes and osteoclasts in vitro. J Cell Biochem. 2019 Oct;120(10):16741-16749.
[6] Magna M, Hwang GH, McIntosh A, et al. RAGE inhibitor TTP488(Azeliragon) suppresses metastasis in triple-negative breast cancer. npj Breast Cancer. 2023;9:59.
[7] Lai MC, Tzeng YC, Liu WY, et al. Phycocyanobilin as a Functional Food-Derived Nutraceutical Candidate for Modulating the RAGE/NOX4 Axis in Neurodegenerative Disorders. Nutrients. 2026 Feb 13;18(4):617.
[8] Davis HM, Essex AL, Valdez S, et al. Short-term pharmacologic RAGE inhibition differentially effects bone and skeletal muscle in middle-aged mice. Bone. 2019 Jul;124:89-102.
[9] Oliveira AL, Medeiros ML, Campos ATP, et al. The RAGE Inhibitor TTP488(Azeliragon) Improves Diabetic Bladder Dysfunction in Leptin-Deficient Obese Mice. Antioxidants. 2025 Jun 27;14(7):793.
[10] Yang L, Liu Y, Wang Y, et al. Azeliragon ameliorates Alzheimer's disease via the Janus tyrosine kinase and signal transducer and activator of transcription signaling pathway. Clinics (Sao Paulo). 2021;76:e2348.