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Purity: ≥98%
Azeliragon (also known as TTP488 and PF-04494700) is a potent and orally bioavailable RAGE (Receptor for Advanced Glycation End products) inhibitor that has the potential for the treatment of mild-to-moderate Alzheimer's disease and cerebral amyloid angiopathy. RAGE is a pattern recognition receptor that affects the movement of amyloid (a biomarker for Alzheimer's disease) into the brain. In preclinical studies, azeliragon decreased brain amyloid in mice and improved their performance on behavior tests. Azeliragon has been shown to be involved in adaptive immune responses. It is currently in Phase 3 clinical trial.
| Targets |
RAGE (receptor for advanced glycation end products)
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|---|---|
| ln Vitro |
Treatment with azeliragon (4 nM; 16 hours) inhibits T cells in wild type (WT) mice, but not T cells with deleted receptors (RAGE-/- mice), nor does it significantly lower IFN-γ production[3].
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| ln Vivo |
Islets were isolated from young prediabetic NOD/LtJ mice and transplanted into NOD mice with spontaneous diabetes; islets were isolated from WT BALB/c mice and transplanted into B6 mice with diabetes. Azeliragon (100 mcg/d; intraperitoneal injection; every day) treatment reduces syngeneic islet graft and islet allograft in NOD and B6 mice[3].
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| Enzyme Assay |
Using serum from uremic pigs with chronic renal insufficiency, our results show that KLF2 expression is suppressed by the uremic milieu and individual uremic solutes in vitro. Specifically, KLF2 expression is significantly decreased in human umbilical vein endothelial cells after treatment with uremic porcine serum or carboxymethyllysine‐modified albumin, an advanced glycation end product (AGE) known to induce endothelial dysfunction. AGE‐mediated suppression of KLF2 is dependent on activation of the receptor for AGE, as measured by small interfering RNA knockdown of the receptor for AGE. Furthermore, KLF2 suppression promotes endothelial dysfunction, because adenoviral overexpression of KLF2 inhibits reactive oxygen species production and leukocyte adhesion in human umbilical vein endothelial cells. In addition, the application of hemodynamic shear stress, prolonged serum dialysis, or treatment with the receptor for AGE antagonist azeliragon (TTP488) is sufficient to prevent KLF2 suppression in vitro. [4]
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| Cell Assay |
Cell Viability Assay[3]
Cell Types: Purified T cells from RAGE-/- or WT B6 mice. Tested Concentrations: 4 nM Incubation Duration: 16 hrs (hours) Experimental Results: Inhibited of WT but not RAGE-/- T cells, and Dramatically decreased the level of IFN-γ. |
| Animal Protocol |
Animal/Disease Models: Prediabetic NOD/LtJ (6-7 week old) mice, NOD mice with spontaneous diabetes, WT balb/c (Bagg ALBino) mouse (8-10 week old ) and B6 mice with diabetes [3].
Doses: 100 mcg/d Route of Administration: intraperitoneal (ip)injection; every day Experimental Results: Prolonged islet auto and allograft survival. |
| References |
[1]. Burstein AH, et al. Assessment of Azeliragon QTc Liability Through Integrated, Model-Based Concentration QTc Analysis. Clin Pharmacol Drug Dev. 2019 May;8(4):426-435.
[2]. Bongarzone S, et al. Targeting the Receptor for Advanced Glycation Endproducts (RAGE): A Medicinal Chemistry Perspective. J Med Chem. 2017 Sep 14;60(17):7213-7232. [3]. Chen Y, et al. RAGE ligation affects T cell activation and controls T cell differentiation. J Immunol. 2008 Sep 15;181(6):4272-8. [4]. J Am Heart Assoc. 2018 Jan; 7(1): e007566. |
| Molecular Formula |
C32H38CLN3O2
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|---|---|---|
| Molecular Weight |
532.12
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| Exact Mass |
531.26525
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| Elemental Analysis |
C, 72.23; H, 7.20; Cl, 6.66; N, 7.90; O, 6.01
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| CAS # |
603148-36-3
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| Related CAS # |
1284150-65-7 (2HCl);603148-36-3
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| Appearance |
White to light yellow solid
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| LogP |
8.3
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| tPSA |
39.52
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| SMILES |
CCN(CC)CCCOC1=CC=C(C2=CN(C3=CC=C(OC4=CC=C(Cl)C=C4)C=C3)C(CCCC)=N2)C=C1
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| InChi Key |
KJNNWYBAOPXVJY-UHFFFAOYSA-N
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| 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
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| Chemical Name |
3-(4-(2-butyl-1-(4-(4-chlorophenoxy)phenyl)-1H-imidazol-4-yl)phenoxy)-N,N-diethylpropan-1-amine
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.70 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.70 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.70 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8793 mL | 9.3964 mL | 18.7928 mL | |
| 5 mM | 0.3759 mL | 1.8793 mL | 3.7586 mL | |
| 10 mM | 0.1879 mL | 0.9396 mL | 1.8793 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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