Azeliragon

Azeliragon (TTP488) is an orally bioavailable small molecule that inhibits the receptor for advanced glycation endproducts (RAGE). A phase 2/3 clinical trial for azeliragon as a potential treatment of mild Alzheimer’s disease (AD) in patients with type 2 diabetes is being planned.

RAGE is an immunoglobulin-like cell surface receptor that is overexpressed in brain tissues of patients with AD. The multiligand nature of RAGE is highlighted by its ability to bind diverse ligands such as advanced glycation end-products (AGEs), linked to diabetic complications and β-amyloid fibrils, a hallmark of AD. The association between type 2 diabetes and AD is well documented. A linear correlation between circulating hemoglobin A1c (HbA1c) levels and cognitive decline has been demonstrated in the English Longitudinal Study of Ageing. 

 

RAGE Mechanism Publications
  1. Walker D, Lue LF, Paul G, Patel A, Sabbagh MN. Receptor for advanced glycation endproduct modulators: a new therapeutic target in Alzheimer’s disease. Expert Opin Investig Drugs. 2015 Mar;24(3):393-9. Abstract link:  http://www.ncbi.nlm.nih.gov/pubmed/25586103
  2. Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, et al. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med. 2005 Nov;83(11):876-86. Abstract link:  http://www.ncbi.nlm.nih.gov/pubmed/16133426
  3. Li XH, Lv BL, Xie JZ et al.  AGEs induce Alzheimer’s-like tau pathology and memory deficit via RAGE-mediated GSK-3 activation.   Neurobiology of Aging 2012;33:1400-14210. Abstract link: http://www.ncbi.nlm.nih.gov/pubmed/21450369
  4. Lue LF, Walker DG, Jacobson S, Sabbagh M.  Receptor for advanced glycation endproducts: its role in Alzheimer’s disease and other neurologic diseases.   Future Neurol 2009;4(2):167-177. Abstract link:    http://www.ncbi.nlm.nih.gov/pubmed/19885375
  5. Perrone L, Sbai O, Nawroth PP, Bierhaus A.  The complexity of sporadic Alzheimer’s disease pathogenesis: The role of RAGE as therapeutic target to promote neuroprotection by inhibiting neurovascular dysfunction.  In J Alzheimers Dis 2012;;2012:734956. doi: 10.1155/2012/734956. Epub 2012 Mar 11. Abstract link:  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310161/
  6. Schmidt AM, Sahagan B, Nelson RB, Selmer J, Rothlein R, Bell JM. The role of RAGE in amyloid-beta peptide-mediated pathology in Alzheimer’s disease. Curr Opin Investig Drugs. 2009 Jul;10(7):672-80.  Abstract link:  http://www.ncbi.nlm.nih.gov/pubmed/19579173
  7. Stern D, Yan SD, Yan SF, Schmidt AM. Receptor for advanced glycation endproducts: a multiligand receptor magnifying cell stress in diverse pathologic settings. Adv Drug Deliv Rev. 2002;54(12):1615-25. Abstract link: http://www.ncbi.nlm.nih.gov/pubmed/12453678
  8. Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 1996 Aug;382(6593):685–691. Abstract link:  http://www.ncbi.nlm.nih.gov/pubmed/8751438
  9. Yan SD, Chen X, Walker DG, Schmidt AM, Arancio O, Lue LF. RAGE: a potential target for Abeta-mediated cellular perturbation in Alzheimer’s disease. Curr Mol Med. 2007;7(8):735-42. Abstract Link :  http://www.ncbi.nlm.nih.gov/pubmed/18331231
  10. Yan SD, Bierhaus A, Nawroth PP, Stern DM. RAGE and Alzheimer’s disease: a progression factor for amyloid-beta-induced cellular perturbation? J Alzheimers Dis. 2009;16(4):833-43. Abstract link:  http://www.ncbi.nlm.nih.gov/pubmed/19387116

 

Publications

Links to the following publications and presentations, which are located on outside websites, are provided for informational purposes only and do not constitute the opinions or views of vTv Therapeutics

Presentations and Posters

Links to the following publications and presentations, which are located on outside websites, are provided for informational purposes only and do not constitute the opinions or views of vTv Therapeutics