WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H319637
CAS#: 603148-36-3 (free base)
Description: Azeliragon free base, also known as TTP488 and PF-04494700, is a potent and orally active RAGE inhibitor. RAGE (receptor for advanced glycation endproducts) is a pattern recognition receptor, which affects the movement of amyloid, an Alzheimer's-associated protein, into the brain. In preclinical studies, azeliragon decreased brain amyloid in mice and improved their performance on behavior tests. Azeliragon is a promising agent for for Alzheimer's disease and cerebral amyloid angiopathy.
Hodoodo Cat#: H319637
Name: Azeliragon free base
CAS#: 603148-36-3 (free base)
Chemical Formula: C32H38ClN3O2
Exact Mass: 531.27
Molecular Weight: 532.125
Elemental Analysis: C, 72.23; H, 7.20; Cl, 6.66; N, 7.90; O, 6.01
Related CAS #: 1284150-65-7 (2HCl) 603148-36-3 (free base)
Synonym: TTP488; TTP-488; TTP 488; PF-04494700; PF 04494700; PF04494700; Azeliragon
IUPAC/Chemical Name: 3-(4-(2-butyl-1-(4-(4-chlorophenoxy)phenyl)-1H-imidazol-4-yl)phenoxy)-N,N-diethylpropan-1-amine
InChi Key: KJNNWYBAOPXVJY-UHFFFAOYSA-N
InChi Code: InChI=1S/C32H38ClN3O2/c1-4-7-9-32-34-31(25-10-16-28(17-11-25)37-23-8-22-35(5-2)6-3)24-36(32)27-14-20-30(21-15-27)38-29-18-12-26(33)13-19-29/h10-21,24H,4-9,22-23H2,1-3H3
SMILES Code: CCN(CC)CCCOC1=CC=C(C2=CN(C3=CC=C(OC4=CC=C(Cl)C=C4)C=C3)C(CCCC)=N2)C=C1
Appearance: White to off-white solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
More Info:
| Biological target: | Azeliragon (TTP488) is an orally bioavailable inhibitor of the receptor for advanced glycation end products (RAGE). |
| In vitro activity: | Finally, this study investigated if administration of novel RAGE antagonists was capable of restoring KLF2 expression and improving markers of EC function. HUVECs were treated with increasing concentrations of the RAGE antagonist azeliragon (TTP488) in the presence or absence of CML-BSA. TTP488 prevented the suppression of KLF2 mRNA by CML-BSA with an EC50 of 1.9 µmol/L compared with vehicle-treated cells (Figure 6A). At concentrations >5 µmol/L, TTP488 completely restored KLF2 expression to baseline levels. This study also ascertained whether TTP488 could improve endothelial function in the presence of the complete uremic milieu (Figure 6B through 6E). In the presence of uremic serum for 24 hours, TTP488 did not increase the expression of KLF2 or its downstream targets, endothelial NO synthase and thrombomodulin, compared with cells without TTP488 (Figure 6B through 6D). However, pretreatment with the RAGE antagonist did reduce the expression of vascular cell adhesion molecule 1 by half in cells exposed to uremic serum (P=0.0068; Figure 6E). Reference: J Am Heart Assoc. 2018 Jan; 7(1): e007566. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778969/ |
| In vivo activity: | The results showed that TTP488 significantly improved the spatial memory of rats, reduced the NLRP1 levels, and decreased the neuronal cell damage. Furthermore, to detect the inhibition of NLRP1 inflammasome activation in TTP488, this study used LPS and the oeNLRP1 construct, which reversed the effects of TTP488. Thus, these findings show that the anti-inflammatory function of TTP488 may be achieved via the inhibition of NLRP1 inflammasome activation.az Reference: Clinics (Sao Paulo). 2021; 76: e2348. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920406/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 50.3 | 94.58 | |
| DMF | 5.0 | 9.40 | |
| DMF:PBS (pH 7.2) (1:2) | 0.3 | 0.62 | |
| Ethanol | 50.5 | 94.90 |
The following data is based on the product molecular weight 532.13 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Davis HM, Valdez S, Gomez L, Malicky P, White FA, Subler MA, Windle JJ, Bidwell JP, Bruzzaniti A, Plotkin LI. High mobility group box 1 protein regulates osteoclastogenesis through direct actions on osteocytes and osteoclasts in vitro. J Cell Biochem. 2019 Oct;120(10):16741-16749. doi: 10.1002/jcb.28932. Epub 2019 May 20. PMID: 31106449; PMCID: PMC6713577. 2. Saum K, Campos B, Celdran-Bonafonte D, Nayak L, Sangwung P, Thakar C, Roy-Chaudhury P, Owens AP Iii PhD. Uremic Advanced Glycation End Products and Protein-Bound Solutes Induce Endothelial Dysfunction Through Suppression of Krüppel-Like Factor 2. J Am Heart Assoc. 2018 Jan 4;7(1):e007566. doi: 10.1161/JAHA.117.007566. PMID: 29301761; PMCID: PMC5778969. 3. Yang L, Liu Y, Wang Y, Li J, Liu N. Azeliragon ameliorates Alzheimer's disease via the Janus tyrosine kinase and signal transducer and activator of transcription signaling pathway. Clinics (Sao Paulo). 2021 Mar 8;76:e2348. doi: 10.6061/clinics/2021/e2348. PMID: 33681944; PMCID: PMC7920406. 4. Davis HM, Essex AL, Valdez S, Deosthale PJ, Aref MW, Allen MR, Bonetto A, Plotkin LI. Short-term pharmacologic RAGE inhibition differentially affects bone and skeletal muscle in middle-aged mice. Bone. 2019 Jul;124:89-102. doi: 10.1016/j.bone.2019.04.012. Epub 2019 Apr 24. PMID: 31028960; PMCID: PMC6543548. |
| In vitro protocol: | 1. Davis HM, Valdez S, Gomez L, Malicky P, White FA, Subler MA, Windle JJ, Bidwell JP, Bruzzaniti A, Plotkin LI. High mobility group box 1 protein regulates osteoclastogenesis through direct actions on osteocytes and osteoclasts in vitro. J Cell Biochem. 2019 Oct;120(10):16741-16749. doi: 10.1002/jcb.28932. Epub 2019 May 20. PMID: 31106449; PMCID: PMC6713577. 2. Saum K, Campos B, Celdran-Bonafonte D, Nayak L, Sangwung P, Thakar C, Roy-Chaudhury P, Owens AP Iii PhD. Uremic Advanced Glycation End Products and Protein-Bound Solutes Induce Endothelial Dysfunction Through Suppression of Krüppel-Like Factor 2. J Am Heart Assoc. 2018 Jan 4;7(1):e007566. doi: 10.1161/JAHA.117.007566. PMID: 29301761; PMCID: PMC5778969. |
| In vivo protocol: | 1. Yang L, Liu Y, Wang Y, Li J, Liu N. Azeliragon ameliorates Alzheimer's disease via the Janus tyrosine kinase and signal transducer and activator of transcription signaling pathway. Clinics (Sao Paulo). 2021 Mar 8;76:e2348. doi: 10.6061/clinics/2021/e2348. PMID: 33681944; PMCID: PMC7920406. 2. Davis HM, Essex AL, Valdez S, Deosthale PJ, Aref MW, Allen MR, Bonetto A, Plotkin LI. Short-term pharmacologic RAGE inhibition differentially affects bone and skeletal muscle in middle-aged mice. Bone. 2019 Jul;124:89-102. doi: 10.1016/j.bone.2019.04.012. Epub 2019 Apr 24. PMID: 31028960; PMCID: PMC6543548. |
1: Burstein AH, Sabbagh M, Andrews R, Valcarce C, Dunn I, Altstiel L. 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. doi: 10.14283/jpad.2018.18. PMID: 29616709.
2: Kong W, Zhu L, Li T, Chen J, Fan B, Ji W, Zhang C, Cai X, Hu C, Sun X, Cao P. Azeliragon inhibits PAK1 and enhances the therapeutic efficacy of AKT inhibitors in pancreatic cancer. Eur J Pharmacol. 2023 Jun 5;948:175703. doi: 10.1016/j.ejphar.2023.175703. Epub 2023 Apr 5. PMID: 37028543.
3: Joshi AA, Wu Y, Deng S, Preston-Hurlburt P, Forbes JM, Herold KC. RAGE antagonism with azeliragon improves xenograft rejection by T cells in humanized mice. Clin Immunol. 2022 Dec;245:109165. doi: 10.1016/j.clim.2022.109165. Epub 2022 Oct 17. PMID: 36257528.
4: Xie J, Xu H, Wu X, Xie Y, Lu X, Wang L. Design, synthesis and anti-TNBC activity of Azeliragon triazole analogues. Bioorg Med Chem Lett. 2021 Dec 15;54:128444. doi: 10.1016/j.bmcl.2021.128444. Epub 2021 Nov 9. PMID: 34763082.
5: Burstein AH, Brantley SJ, Dunn I, Altstiel LD, Schmith V. Assessment of Azeliragon QTc Liability Through Integrated, Model-Based Concentration QTc Analysis. Clin Pharmacol Drug Dev. 2019 May;8(4):426-435. doi: 10.1002/cpdd.689. Epub 2019 Apr 1. PMID: 30934161.
6: Yang L, Liu Y, Wang Y, Li J, Liu N. Azeliragon ameliorates Alzheimer's disease via the Janus tyrosine kinase and signal transducer and activator of transcription signaling pathway. Clinics (Sao Paulo). 2021 Mar 8;76:e2348. doi: 10.6061/clinics/2021/e2348. PMID: 33681944; PMCID: PMC7920406.
7: Ma S, Nakamura Y, Hisaoka-Nakashima K, Morioka N. Blockade of receptor for advanced glycation end-products with azeliragon ameliorates streptozotocin- induced diabetic neuropathy. Neurochem Int. 2023 Feb;163:105470. doi: 10.1016/j.neuint.2022.105470. Epub 2022 Dec 26. PMID: 36581174.
8: Godyń J, Jończyk J, Panek D, Malawska B. Therapeutic strategies for Alzheimer's disease in clinical trials. Pharmacol Rep. 2016 Feb;68(1):127-38. doi: 10.1016/j.pharep.2015.07.006. Epub 2015 Aug 5. PMID: 26721364.
9: Kim EY, Dryer SE. RAGE and αVβ3-integrin are essential for suPAR signaling in podocytes. Biochim Biophys Acta Mol Basis Dis. 2021 Oct 1;1867(10):166186. doi: 10.1016/j.bbadis.2021.166186. Epub 2021 Jun 22. PMID: 34166766; PMCID: PMC8328937.
10: Davis HM, Essex AL, Valdez S, Deosthale PJ, Aref MW, Allen MR, Bonetto A, Plotkin LI. Short-term pharmacologic RAGE inhibition differentially affects bone and skeletal muscle in middle-aged mice. Bone. 2019 Jul;124:89-102. doi: 10.1016/j.bone.2019.04.012. Epub 2019 Apr 24. PMID: 31028960; PMCID: PMC6543548.
11: Reddy VP, Aryal P, Soni P. RAGE Inhibitors in Neurodegenerative Diseases. Biomedicines. 2023 Apr 9;11(4):1131. doi: 10.3390/biomedicines11041131. PMID: 37189749; PMCID: PMC10136230.
12: Rojas M, Chávez-Castillo M, Bautista J, Ortega Á, Nava M, Salazar J, Díaz- Camargo E, Medina O, Rojas-Quintero J, Bermúdez V. Alzheimer's disease and type 2 diabetes mellitus: Pathophysiologic and pharmacotherapeutics links. World J Diabetes. 2021 Jun 15;12(6):745-766. doi: 10.4239/wjd.v12.i6.745. PMID: 34168725; PMCID: PMC8192246.
13: Wautier MP, Guillausseau PJ, Wautier JL. Activation of the receptor for advanced glycation end products and consequences on health. Diabetes Metab Syndr. 2017 Oct-Dec;11(4):305-309. doi: 10.1016/j.dsx.2016.09.009. Epub 2016 Sep 4. PMID: 27612394.
14: Panza F, Seripa D, Solfrizzi V, Imbimbo BP, Lozupone M, Leo A, Sardone R, Gagliardi G, Lofano L, Creanza BC, Bisceglia P, Daniele A, Bellomo A, Greco A, Logroscino G. Emerging drugs to reduce abnormal β-amyloid protein in Alzheimer's disease patients. Expert Opin Emerg Drugs. 2016 Dec;21(4):377-391. doi: 10.1080/14728214.2016.1241232. Epub 2016 Oct 6. PMID: 27678025.
15: Zhang C, Wang L, Xu Y, Huang Y, Huang J, Zhu J, Wang W, Li W, Sun A, Li X, Zhang H, Li J. Discovery of novel dual RAGE/SERT inhibitors for the potential treatment of the comorbidity of Alzheimer's disease and depression. Eur J Med Chem. 2022 Jun 5;236:114347. doi: 10.1016/j.ejmech.2022.114347. Epub 2022 Apr 6. PMID: 35430560.
16: Li J, Wang K, Huang B, Li R, Wang X, Zhang H, Tang H, Chen X. The receptor for advanced glycation end products mediates dysfunction of airway epithelial barrier in a lipopolysaccharides-induced murine acute lung injury model. Int Immunopharmacol. 2021 Apr;93:107419. doi: 10.1016/j.intimp.2021.107419. Epub 2021 Feb 3. PMID: 33548580.
17: Davis HM, Valdez S, Gomez L, Malicky P, White FA, Subler MA, Windle JJ, Bidwell JP, Bruzzaniti A, Plotkin LI. High mobility group box 1 protein regulates osteoclastogenesis through direct actions on osteocytes and osteoclasts in vitro. J Cell Biochem. 2019 Oct;120(10):16741-16749. doi: 10.1002/jcb.28932. Epub 2019 May 20. PMID: 31106449; PMCID: PMC6713577.
18: Saum K, Campos B, Celdran-Bonafonte D, Nayak L, Sangwung P, Thakar C, Roy- Chaudhury P, Owens AP Iii PhD. Uremic Advanced Glycation End Products and Protein-Bound Solutes Induce Endothelial Dysfunction Through Suppression of Krüppel-Like Factor 2. J Am Heart Assoc. 2018 Jan 4;7(1):e007566. doi: 10.1161/JAHA.117.007566. PMID: 29301761; PMCID: PMC5778969.
19: Kozlyuk N, Gilston BA, Salay LE, Gogliotti RD, Christov PP, Kim K, Ovee M, Waterson AG, Chazin WJ. A fragment-based approach to discovery of Receptor for Advanced Glycation End products inhibitors. Proteins. 2021 Nov;89(11):1399-1412. doi: 10.1002/prot.26162. Epub 2021 Jul 2. PMID: 34156100; PMCID: PMC8492516.
20: Xue J, Jia P, Zhang D, Yao Z. TTP488 ameliorates NLRP3-associated inflammation, viability, apoptosis, and ROS production in an Alzheimer's disease cell model by mediating the JAK1/STAT3/NFκB/IRF3 pathway. Cell Biochem Funct. 2021 Jun;39(4):555-561. doi: 10.1002/cbf.3623. Epub 2021 Mar 16. PMID: 33724512.
