RAGE (receptor)

Last updated
AGER
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases AGER , Ager, RAGE, SCARJ1, advanced glycosylation end product-specific receptor, advanced glycosylation end-product specific receptor, sRAGE
External IDs OMIM: 600214 MGI: 893592 HomoloGene: 883 GeneCards: AGER
Orthologs
SpeciesHumanMouse
Entrez

177

11596

Ensembl

ENSMUSG00000015452

UniProt

Q15109

Q62151

RefSeq (mRNA)

NM_001271422
NM_001271423
NM_001271424
NM_007425

RefSeq (protein)

NP_001258351
NP_001258352
NP_001258353
NP_031451

Location (UCSC) Chr 6: 32.18 – 32.18 Mb Chr 17: 34.82 – 34.82 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Schematic of the relation between an immunoglobulin and RAGE IgG-RAGE.jpg
Schematic of the relation between an immunoglobulin and RAGE
Schematic of the RAGE gene and its products RAGEvariants.jpg
Schematic of the RAGE gene and its products

RAGE (receptor for advanced glycation endproducts), also called AGER, is a 35 kilodalton transmembrane receptor of the immunoglobulin super family which was first characterized in 1992 by Neeper et al. [5] Its name comes from its ability to bind advanced glycation endproducts (AGE), which include chiefly glycoproteins, the glycans of which have been modified non-enzymatically through the Maillard reaction. In view of its inflammatory function in innate immunity and its ability to detect a class of ligands through a common structural motif, RAGE is often referred to as a pattern recognition receptor. RAGE also has at least one other agonistic ligand: high mobility group protein B1 (HMGB1). HMGB1 is an intracellular DNA-binding protein important in chromatin remodeling which can be released by necrotic cells passively, and by active secretion from macrophages, natural killer cells, and dendritic cells.

The interaction between RAGE and its ligands is thought to result in pro-inflammatory gene activation. [6] [7] Due to an enhanced level of RAGE ligands in diabetes or other chronic disorders, this receptor is hypothesised to have a causative effect in a range of inflammatory diseases such as diabetic complications, Alzheimer's disease and even some tumors.

Isoforms of the RAGE protein, which lack the transmembrane and the signaling domain (commonly referred to as soluble RAGE or sRAGE) are hypothesized to counteract the detrimental action of the full-length receptor and are hoped to provide a means to develop a cure against RAGE-associated diseases.

Gene and polymorphisms

The RAGE gene lies within the major histocompatibility complex (MHC class III region) on chromosome 6 and comprises 11 exons interlaced by 10 introns. Total length of the gene is about 1400 base pairs (bp) including the promoter region, which partly overlaps with the PBX2 gene. [8] About 30 polymorphisms are known most of which are single-nucleotide polymorphisms. [9]

RNA and alternative splicing

The primary transcript of the human RAGE gene (pre-mRNA) is thought to be alternatively spliced. So far about 6 isoforms including the full length transmembrane receptor have been found in different tissues such as lung, kidney, brain etc. Five of these 6 isoforms lack the transmembrane domain and are thus believed to be secreted from cells. Generally these isoforms are referred to as sRAGE (soluble RAGE) or esRAGE (endogenous secretory RAGE). One of the isoforms lacks the V-domain and is thus believed not to be able to bind RAGE ligands.

Structure

RAGE exists in the body in two forms: a membrane-bound form known as mRAGE, and a soluble form, known as sRAGE. mRAGE has three domains, and sRAGE has only the extracellular domain. sRAGE is either the product of alternative splicing or the product of proteolytic cleavage of mRAGE. [10]

The full receptor consists of the following domains: The cytosolic domain, which is responsible for signal transduction, the transmembrane domain which anchors the receptor in the cell membrane, the variable domain which binds the RAGE ligands, and two constant domains.[ citation needed ]

Ligands

RAGE is able to bind several ligands and therefore is referred to as a pattern-recognition receptor. Ligands which have so far been found to bind RAGE are:

RAGE and disease

RAGE has been linked to several chronic diseases, which are thought to result from vascular damage. The pathogenesis is hypothesized to include ligand binding, upon which RAGE signals activation of nuclear factor kappa B (NF-κB). NF-κB controls several genes involved in inflammation. RAGE itself is upregulated by NF-κB. Given a condition in which there is a large amount of RAGE ligands (e.g. AGE in diabetes or amyloid-β-protein in Alzheimer's disease) this establishes a positive feed-back cycle, which leads to chronic inflammation. This chronic condition is then believed to alter the micro- and macrovasculature, resulting in organ damage or even organ failure. [16] However, whilst RAGE is up-regulated in inflammatory conditions, it is down-regulated in lung cancer and pulmonary fibrosis. [10] Diseases that have been linked to RAGE are: [ citation needed ]

RAGE is expressed at the highest levels in the lung compared to other tissues, in particular in alveolar type I cells, and is lost in idiopathic pulmonary fibrosis (IPF) indicating that expression and regulation of RAGE in the pulmonary system differs from that in the vascular system. Blockade/knockdown of RAGE resulted in impaired cell adhesion, and increased cell proliferation and migration [22]

Inhibitors

A number of small molecule RAGE inhibitors or antagonists have been reported. [23] [24] [25] [26]

Azeliragon
vTv Therapeutics (formerly TransTech Pharma) sponsored a Phase 3 clinical trial of their RAGE inhibitor Azeliragon (TTP488) for mild Alzheimer's disease. [27] [28] These trials were halted in 2018. [29]

AGE receptors

Besides RAGE there are other receptors which are believed to bind advanced glycation endproducts. However, these receptors could play a role in the removal of AGE rather than in signal transduction as is the case for RAGE. Other AGE receptors are:

Related Research Articles

Glycation is the covalent attachment of a sugar to a protein, lipid or nucleic acid molecule. Typical sugars that participate in glycation are glucose, fructose, and their derivatives. Glycation is the non-enzymatic process responsible for many complications in diabetes mellitus and is implicated in some diseases and in aging. Glycation end products are believed to play a causative role in the vascular complications of diabetes mellitus.

Advanced glycation end products (AGEs) are proteins or lipids that become glycated as a result of exposure to sugars. They are a bio-marker implicated in aging and the development, or worsening, of many degenerative diseases, such as diabetes, atherosclerosis, chronic kidney disease, and Alzheimer's disease.

<span class="mw-page-title-main">Low-density lipoprotein receptor-related protein 8</span> Cell surface receptor, part of the low-density lipoprotein receptor family

Low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2), is a protein that in humans is encoded by the LRP8 gene. ApoER2 is a cell surface receptor that is part of the low-density lipoprotein receptor family. These receptors function in signal transduction and endocytosis of specific ligands. Through interactions with one of its ligands, reelin, ApoER2 plays an important role in embryonic neuronal migration and postnatal long-term potentiation. Another LDL family receptor, VLDLR, also interacts with reelin, and together these two receptors influence brain development and function. Decreased expression of ApoER2 is associated with certain neurological diseases.

<span class="mw-page-title-main">HMGB1</span> Mammalian protein found in Homo sapiens

High mobility group box 1 protein, also known as high-mobility group protein 1 (HMG-1) and amphoterin, is a protein that in humans is encoded by the HMGB1 gene.

<span class="mw-page-title-main">Coagulation factor II receptor</span> Mammalian protein found in Homo sapiens

Proteinase-activated receptor 1 (PAR1) also known as protease-activated receptor 1 or coagulation factor II (thrombin) receptor is a protein that in humans is encoded by the F2R gene. PAR1 is a G protein-coupled receptor and one of four protease-activated receptors involved in the regulation of thrombotic response. Highly expressed in platelets and endothelial cells, PAR1 plays a key role in mediating the interplay between coagulation and inflammation, which is important in the pathogenesis of inflammatory and fibrotic lung diseases. It is also involved both in disruption and maintenance of endothelial barrier integrity, through interaction with either thrombin or activated protein C, respectively.

<span class="mw-page-title-main">EPH receptor B2</span> Protein-coding gene in the species Homo sapiens

Ephrin type-B receptor 2 is a protein that in humans is encoded by the EPHB2 gene.

<span class="mw-page-title-main">TAS2R1</span> Member of the 25 known human bitter taste receptors

Taste receptor type 2 member 1 (TAS2R1/T2R1) is a protein that in humans is encoded by the TAS2R1 gene. It belongs to the G protein-coupled receptor (GPCR) family and is related to class A-like GPCRs, they contain 7 transmembrane helix bundles and short N-terminus loop. Furthermore, TAS2R1 is member of the 25 known human bitter taste receptors, which enable the perception of bitter taste in the mouth cavity. Increasing evidence indicates a functional role of TAS2Rs in extra-oral tissues.

<span class="mw-page-title-main">TAS2R46</span> Protein-coding gene in the species Homo sapiens

Taste receptors for bitter substances (T2Rs/TAS2Rs) belong to the family of G-protein coupled receptors and are related to class A-like GPCRs. There are 25 known T2Rs in humans responsible for bitter taste perception.

<span class="mw-page-title-main">Colony stimulating factor 1 receptor</span> Protein-coding gene in the species Homo sapiens

Colony stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115, is a cell-surface protein encoded by the human CSF1R gene. CSF1R is a receptor that can be activated by two ligands: colony stimulating factor 1 (CSF-1) and interleukin-34 (IL-34). CSF1R is highly expressed in myeloid cells, and CSF1R signaling is necessary for the survival, proliferation, and differentiation of many myeloid cell types in vivo and in vitro. CSF1R signaling is involved in many diseases and is targeted in therapies for cancer, neurodegeneration, and inflammatory bone diseases.

<span class="mw-page-title-main">TREM1</span> Protein-coding gene in the species Homo sapiens

Triggering receptor expressed on myeloid cells 1 (TREM1) an immunoglobulin (Ig) superfamily transmembrane protein that, in humans, is encoded by the TREM1 gene. TREM1 is constitutively expressed on the surface of peripheral blood monocytes and neutrophils, and upregulated by toll-like receptor (TLR) ligands; activation of TREM1 amplifies immune responses.

<span class="mw-page-title-main">RAGE (gene)</span> Protein-coding gene in the species Homo sapiens

MAPK/MAK/MRK overlapping kinase is an enzyme that in humans is encoded by the RAGE gene.

<span class="mw-page-title-main">PTPRN2</span> Protein-coding gene in the species Homo sapiens

Receptor-type tyrosine-protein phosphatase N2 (R-PTP-N2) also known as islet cell autoantigen-related protein (ICAAR) and phogrin is an enzyme that in humans is encoded by the PTPRN2 gene. PTPRN and PTPRN2 are both found to be major autoantigens associated with insulin-dependent diabetes mellitus.

<span class="mw-page-title-main">HAVCR2</span> Protein-coding gene in the species Homo sapiens

Hepatitis A virus cellular receptor 2 (HAVCR2), also known as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), is a protein that in humans is encoded by the HAVCR2 (TIM-3)gene. HAVCR2 was first described in 2002 as a cell surface molecule expressed on IFNγ producing CD4+ Th1 and CD8+ Tc1 cells. Later, the expression was detected in Th17 cells, regulatory T-cells, and innate immune cells. HAVCR2 receptor is a regulator of the immune response.

<span class="mw-page-title-main">DDOST</span> Protein-coding gene in the species Homo sapiens

Dolichyl-diphosphooligosaccharide—protein glycosyltransferase 48 kDa subunit is an enzyme that in humans is encoded by the DDOST gene.

<span class="mw-page-title-main">TREM2</span> Protein-coding gene in the species Homo sapiens

Triggering receptor expressed on myeloid cells 2(TREM2) is a protein that in humans is encoded by the TREM2 gene. TREM2 is expressed on macrophages, immature monocyte-derived dendritic cells, osteoclasts, and microglia, which are immune cells in the central nervous system. In the liver, TREM2 is expressed by several cell types, including macrophages, that respond to injury. In the intestine, TREM2 is expressed by myeloid-derived dendritic cells and macrophage. TREM2 is overexpressed in many tumor types and has anti-inflammatory activities. It might therefore be a good therapeutic target.

Damage-associated molecular patterns (DAMPs) are molecules within cells that are a component of the innate immune response released from damaged or dying cells due to trauma or an infection by a pathogen. They are also known as danger signals, and alarmin because they serve as a warning sign for the organism to alert it of any damage or infection to its cells. DAMPs are endogenous danger signals that are discharged to the extracellular space in response to damage to the cell from mechanical trauma or a pathogen. Once a DAMP is released from the cell, it promotes a noninfectious inflammatory response by binding to a pattern-recognition receptor. Inflammation is a key aspect of the innate immune response; it is used to help mitigate future damage to the organism by removing harmful invaders from the affected area and start the healing process. As an example, the cytokine IL-1α is a DAMP that originates within the nucleus of the cell which, once released to the extracellular space, binds to the PRR IL-1R, which in turn initiates an inflammatory response to the trauma or pathogen that initiated the release of IL-1α. In contrast to the noninfectious inflammatory response produced by DAMPs, pathogen-associated molecular patterns initiate and perpetuate the infectious pathogen-induced inflammatory response. Many DAMPs are nuclear or cytosolic proteins with defined intracellular function that are released outside the cell following tissue injury. This displacement from the intracellular space to the extracellular space moves the DAMPs from a reducing to an oxidizing environment, causing their functional denaturation, resulting in their loss of function. Outside of the aforementioned nuclear and cytosolic DAMPs, there are other DAMPs originated from different sources, such as mitochondria, granules, the extracellular matrix, the endoplasmic reticulum, and the plasma membrane.

<span class="mw-page-title-main">Diabetic cardiomyopathy</span> Medical condition

Diabetic cardiomyopathy is a disorder of the heart muscle in people with diabetes. It can lead to inability of the heart to circulate blood through the body effectively, a state known as heart failure(HF), with accumulation of fluid in the lungs or legs. Most heart failure in people with diabetes results from coronary artery disease, and diabetic cardiomyopathy is only said to exist if there is no coronary artery disease to explain the heart muscle disorder.

<span class="mw-page-title-main">Enzo Emanuele</span>

Enzo Emanuele is an Italian clinical pathologist known for his interdisciplinary research in the field of biological psychology. He has studied the biochemical basis of romantic interpersonal attraction and identified the neurotrophin nerve growth factor (NGF) as a key biochemical mediator of falling in love. The implications of this research have been criticized in the popular press. In 2008, his genetic research, which showed an association between serotonin and dopamine receptor gene polymorphisms and certain love traits, was awarded with the International Zdenek Klein Award for Human Ethology from the Charles University in Prague, Czech Republic.

<span class="mw-page-title-main">3-Deoxyglucosone</span> Chemical compound

3-Deoxyglucosone (3DG) is a sugar that is notable because it is a marker for diabetes. 3DG reacts with protein to form advanced glycation end-products (AGEs), which contribute to diseases such as the vascular complications of diabetes, atherosclerosis, hypertension, Alzheimer's disease, inflammation, and aging.

<span class="mw-page-title-main">Argpyrimidine</span> Chemical compound

Argpyrimidine is an organic compound with the chemical formula C11H18N4O3. It is an advanced glycation end-product formed from arginine and methylglyoxal through the Maillard reaction. Argpyrimidine has been studied for its food chemistry purposes and its potential involvement in aging diseases and Diabetes Mellius.

References

  1. 1 2 3 ENSG00000206320, ENSG00000231268, ENSG00000234729, ENSG00000229058, ENSG00000204305, ENSG00000230514 GRCh38: Ensembl release 89: ENSG00000237405, ENSG00000206320, ENSG00000231268, ENSG00000234729, ENSG00000229058, ENSG00000204305, ENSG00000230514 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000015452 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, Elliston K, Stern D, Shaw A (July 1992). "Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins". The Journal of Biological Chemistry. 267 (21): 14998–5004. doi: 10.1016/S0021-9258(18)42138-2 . PMID   1378843.
  6. ↑ Bierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert PM, Chen J, Hong M, Luther T, Henle T, Klöting I, Morcos M, Hofmann M, Tritschler H, Weigle B, Kasper M, Smith M, Perry G, Schmidt AM, Stern DM, Häring HU, Schleicher E, Nawroth PP (December 2001). "Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB". Diabetes. 50 (12): 2792–808. doi: 10.2337/diabetes.50.12.2792 . PMID   11723063.
  7. ↑ Gasparotto, J; Girardi, CS; Somensi, N; Ribeiro, CT; Moreira, JCF; Michels, M; Sonai, B; Rocha, M; Steckert, AV; Barichello, T; Quevedo, J; Dal-Pizzol, F; Gelain, DP (Nov 2017). "Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment". J Biol Chem. 293 (1): 226–244. doi: 10.1074/jbc.M117.786756 . PMC   5766916 . PMID   29127203.
  8. ↑ Hudson BI, Stickland MH, Futers TS, Grant PJ (June 2001). "Effects of novel polymorphisms in the RAGE gene on transcriptional regulation and their association with diabetic retinopathy". Diabetes. 50 (6): 1505–11. doi: 10.2337/diabetes.50.6.1505 . PMID   11375354.
  9. ↑ Hudson BI, Hofman MA, Bucciarelli L, Wendt T, Moser B, Lu Y, Qu W, Stern DM, D'Agati V, Yan SD, Yan SF, Grant PJ (2002). "Glycation and diabetes: The RAGE connection" (PDF). Current Science. 83 (12): 1515–1521.
  10. 1 2 3 Oczypok, EA; Perkins, TN; Oury, TD (June 2017). "All the "RAGE" in lung disease: The receptor for advanced glycation endproducts (RAGE) is a major mediator of pulmonary inflammatory responses". Paediatric Respiratory Reviews. 23: 40–49. doi:10.1016/j.prrv.2017.03.012. PMC   5509466 . PMID   28416135.
  11. ↑ Ibrahim ZA, Armour CL, Phipps S, Sukkar MB (December 2013). "RAGE and TLRs: relatives, friends or neighbours?". Molecular Immunology. 56 (4): 739–44. doi:10.1016/j.molimm.2013.07.008. PMID   23954397.
  12. ↑ Penumutchu SR, Chou RH, Yu C (2014). "Structural insights into calcium-bound S100P and the V domain of the RAGE complex". PLOS ONE. 9 (8): e103947. Bibcode:2014PLoSO...9j3947P. doi: 10.1371/journal.pone.0103947 . PMC   4118983 . PMID   25084534.
  13. ↑ Penumutchu SR, Chou RH, Yu C (November 2014). "Interaction between S100P and the anti-allergy drug cromolyn". Biochemical and Biophysical Research Communications. 454 (3): 404–9. doi:10.1016/j.bbrc.2014.10.048. PMID   25450399.
  14. ↑ Hermani A, De Servi B, Medunjanin S, Tessier PA, Mayer D (January 2006). "S100A8 and S100A9 activate MAP kinase and NF-kappaB signaling pathways and trigger translocation of RAGE in human prostate cancer cells". Experimental Cell Research. 312 (2): 184–97. doi:10.1016/j.yexcr.2005.10.013. PMID   16297907.
  15. ↑ Dahlmann M, Okhrimenko A, Marcinkowski P, Osterland M, Herrmann P, Smith J, Heizmann CW, Schlag PM, Stein U (May 2014). "RAGE mediates S100A4-induced cell motility via MAPK/ERK and hypoxia signaling and is a prognostic biomarker for human colorectal cancer metastasis". Oncotarget. 5 (10): 3220–33. doi:10.18632/oncotarget.1908. PMC   4102805 . PMID   24952599.
  16. ↑ Gasparotto, J; Ribeiro, CT; da Rosa-Silva, HT; Bortolin, RC; Rabelo, TK; Peixoto, DO; Moreira, JCF; Gelain, DP (May 2019). "Systemic Inflammation Changes the Site of RAGE Expression from Endothelial Cells to Neurons in Different Brain Areas". Mol Neurobiol. 56 (5): 3079–3089. doi:10.1007/s12035-018-1291-6. hdl: 11323/1858 . PMID   30094805. S2CID   51953478.
  17. ↑ Yammani RR (April 2012). "S100 proteins in cartilage: role in arthritis". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1822 (4): 600–6. doi:10.1016/j.bbadis.2012.01.006. PMC   3294013 . PMID   22266138.
  18. ↑ Kipfmueller, Florian (6 March 2019). "Expression of soluble receptor for advanced glycation end products is associated with disease severity in congenital diaphragmatic hernia". Am J Physiol Lung Cell Mol Physiol. 316 (6): L1061–L1069. doi: 10.1152/ajplung.00359.2018 . PMID   30838867.
  19. ↑ Kuroiwa Y, Takakusagi Y, Kusayanagi T, Kuramochi K, Imai T, Hirayama T, Ito I, Yoshida M, Sakaguchi K, Sugawara F (May 2013). "Identification and characterization of the direct interaction between methotrexate (MTX) and high-mobility group box 1 (HMGB1) protein". PLOS ONE. 8 (5): e63073. Bibcode:2013PLoSO...863073K. doi: 10.1371/journal.pone.0063073 . PMC   3643934 . PMID   23658798.
  20. ↑ Mahajan N, Mahmood S, Jain S, Dhawan V (September 2013). "Receptor for advanced glycation end products (RAGE), inflammatory ligand EN-RAGE and soluble RAGE (sRAGE) in subjects with Takayasu's arteritis". International Journal of Cardiology. 168 (1): 532–4. doi:10.1016/j.ijcard.2013.01.002. PMID   23398829.
  21. ↑ Dwir, Daniella; Giangreco, Basilio; Xin, Lijing; Tenenbaum, Liliane; Cabungcal, Jan-Harry; Steullet, Pascal; Goupil, Audrey; Cleusix, Martine; Jenni, Raoul; Chtarto, Abdelwahed; Baumann, Philipp S.; Klauser, Paul; Conus, Philippe; Tirouvanziam, Rabindra; Cuenod, Michel (November 2020). "MMP9/RAGE pathway overactivation mediates redox dysregulation and neuroinflammation, leading to inhibitory/excitatory imbalance: a reverse translation study in schizophrenia patients". Molecular Psychiatry. 25 (11): 2889–2904. doi:10.1038/s41380-019-0393-5. ISSN   1476-5578.
  22. ↑ Queisser MA, Kouri FM, Königshoff M, Wygrecka M, Schubert U, Eickelberg O, Preissner KT (September 2008). "Loss of RAGE in pulmonary fibrosis: molecular relations to functional changes in pulmonary cell types". American Journal of Respiratory Cell and Molecular Biology. 39 (3): 337–45. doi:10.1165/rcmb.2007-0244OC. PMID   18421017.
  23. ↑ Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, Love R, Perry S, Paquette N, Deane RJ, Thiyagarajan M, Zarcone T, Fritz G, Friedman AE, Miller BL, Zlokovic BV (April 2012). "A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease". The Journal of Clinical Investigation. 122 (4): 1377–92. doi:10.1172/JCI58642. PMC   3314449 . PMID   22406537.
  24. ↑ Han YT, Choi GI, Son D, Kim NJ, Yun H, Lee S, Chang DJ, Hong HS, Kim H, Ha HJ, Kim YH, Park HJ, Lee J, Suh YG (November 2012). "Ligand-based design, synthesis, and biological evaluation of 2-aminopyrimidines, a novel series of receptor for advanced glycation end products (RAGE) inhibitors". Journal of Medicinal Chemistry. 55 (21): 9120–35. doi:10.1021/jm300172z. PMID   22742537.
  25. ↑ Han YT, Kim K, Choi GI, An H, Son D, Kim H, Ha HJ, Son JH, Chung SJ, Park HJ, Lee J, Suh YG (May 2014). "Pyrazole-5-carboxamides, novel inhibitors of receptor for advanced glycation end products (RAGE)". European Journal of Medicinal Chemistry. 79: 128–42. doi:10.1016/j.ejmech.2014.03.072. PMID   24727489.
  26. ↑ Han YT, Kim K, Son D, An H, Kim H, Lee J, Park HJ, Lee J, Suh YG (February 2015). "Fine tuning of 4,6-bisphenyl-2-(3-alkoxyanilino)pyrimidine focusing on the activity-sensitive aminoalkoxy moiety for a therapeutically useful inhibitor of receptor for advanced glycation end products (RAGE)". Bioorganic & Medicinal Chemistry. 23 (3): 579–87. doi:10.1016/j.bmc.2014.12.003. PMID   25533401.
  27. ↑ "Azeliragon". vTv Therapeutics. vTv Therapeutics. Retrieved 23 July 2015.
  28. ↑ Clinical trial number NCT02080364 for "Evaluation of the Efficacy and Safety of Azeliragon (TTP488) in Patients With Mild Alzheimer's Disease (STEADFAST)" at ClinicalTrials.gov
  29. ↑ vTv Halts Trials of Alzheimer's Candidate Azeliragon after Phase III Failure Apr 2018

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