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Azilsartan Medoxomil (TAK 491)

Alias: TAK-491; TAK 491; TAK491; Azilsartan medoxomil; Azilsartan medoxomil potassium; trade name: Edarbi. Ipreziv.
Cat No.:V1793 Purity: ≥98%
Azilsartan Medoxomil (formerly also known as TAK-491), the ester prodrugof Azilsartan (TAK-536),is a potent andorally bioavailable angiotensin II type 1 (AT1) receptor antagonist, inhibits the RAAS, with an IC50 of 2.6 nM.
Azilsartan Medoxomil (TAK 491)
Azilsartan Medoxomil (TAK 491) Chemical Structure CAS No.: 863031-21-4
Product category: RAAS
This product is for research use only, not for human use. We do not sell to patients.
Size Price Stock Qty
10mg
25mg
50mg
100mg
250mg
500mg
1g
Other Sizes

Other Forms of Azilsartan Medoxomil (TAK 491):

  • Azilsartan (TAK-536)
  • Azilsartan D5
  • Azilsartan medoxomil monopotassium (TAK 491)
Official Supplier of:
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Azilsartan Medoxomil (formerly also known as TAK-491), the ester prodrug of Azilsartan (TAK-536), is a potent and orally bioavailable angiotensin II type 1 (AT1) receptor antagonist, inhibits the RAAS, with an IC50 of 2.6 nM. It is used for the treatment of hypertension. Azilsartan lowers blood pressure by blocking the action of angiotensin II. Azilsartan also inhibits the accumulation of AII-induced inositol 1-phosphate (IP1) in the cell-based assay with an IC50 value of 9.2 nM. Azilsartan medoxomil is a useful and attractive new option for lowering BP in patients with essential hypertension, particularly for those not able to tolerate other antihypertensive drugs.

Biological Activity I Assay Protocols (From Reference)
ln Vitro

In vitro activity: Azilsartan medoxomil is a prodrug, which is rapidly converted to the active moiety, azilsartan (TAK-536), by ester hydrolysis in the gut and plasma during absorption after oral administration. Azilsartan selectively blocks the binding of angiotensin II to the AT1 (angiotensin II type 1) receptors found in the vascular smooth muscle and the adrenal gland, thereby promoting vasodilation and a decrease in the effects of aldosterone. Azilsartan is a highly selective antagonist to the AT1 receptor, with an IC50 of 2.6 nM, exhibiting a >10,000-fold affinity for the AT1 receptor compared with the AT2 receptor, and has not shown affinity for other cardiac receptors or ion channels. The inhibitory effect of Azilsartan persists after washout of the free compound (IC50 value of 7.4 nM). Azilsartan also inhibits the accumulation of angiotensin II -induced inositol 1-phosphate (IP1) in the cell-based assay with an IC50 value of 9.2 nM, and this effect is resistant to washout (IC50 value of 81.3 nM).


Kinase Assay: A radioligand binding assay is performed by using human AT1 receptor-coated microplates containing 4.4 to 6.2 fmol of receptors/well (10 μg of membrane protein/well). Membrane-coated wells are incubated with 45 μl of assay buffer (50 mM Tris-HCl, 5 mM MgCl2, 1 mM EDTA, and 0.005% CHAPS, pH 7.4) containing various concentrations of test compounds at room temperature. After 90 min, 5 μl of 125I-Sar1-Ile8-AII (final concentration 0.6 nM) dissolved in assay buffer is added to the wells, and the plate is incubated for 5 h. In each step, the plate is briefly and gently shaken on a plate shaker.


Cell Assay: Measurement of Inositol 1-Phosphate Accumulation. Twentyfour hours after transfections with human AT1-expressing plasmids, the cells are starved by changing the culture medium to starvation buffer (1 mM CaCl2, 0.5 mM MgCl2, 4.2 mM KCl, 146 mM NaCl, 5.5 mM glucose, and 10 mM HEPES, pH 7.3). Then, 5 μl/well of the test compounds dissolved in starvation buffer is added to the cells at the indicated concentrations, and they are pretreated for the indicated times. Two hours after starvation, LiCl is added to a final concentration of 50 mM with or without angiotensin II 10 nM, and the cells are further incubated for the indicated times at 37°C. In washout experiments, the cells are washed once with 100 μl/well of starvation buffer to remove unbound compounds before stimulation with angiotensin II. The accumulation of inositol 1-phosphate (IP1) is measured by using a IP-One Tb kit. The fluorescence resonance energy transfer signal is measured on a plate reader.

ln Vivo
In Koletsky rats, Azilsartan treatment lowers blood pressure, basal plasma insulin concentration and the homeostasis model assessment of insulin resistance index, and inhibited over-increase of plasma glucose and insulin concentrations during oral glucose tolerance test. Azilsartan downregulates 11β-hydroxysteroid dehydrogenase type 1 expression.
Animal Protocol
Suspended in 5% Gum Arabic; 1, 2, and 3 mg/kg; Oral gavage
Male Wistar-Kyoto (WKY) rats, obese Koletsky (fak/fak) rats
ADME/Pharmacokinetics
Absorption, Distribution and Excretion
During absorption, azilsartan medoxomil is hydrolyzed to azilsartan. The parent drug is not detectable in plasma after oral administration. The absolute bioavailability of azilsartan is estimated to be 60%. Tmax ranges from 1.5 to three hours. Steady-state levels of azilsartan are achieved within five days, and no accumulation in plasma occurs with repeated once-daily dosing.
Following oral administration of 14C-labeled azilsartan medoxomil, approximately 55% of radioactivity was recovered in feces and approximately 42% in urine. Of the recovered dose in urine, about 15% was excreted as azilsartan.
The volume of distribution of azilsartan is approximately 16 L. In rats, a minimal amount of radiolabelled drug crossed the blood-brain barrier. Azilsartan crossed the placental barrier in pregnant rats and was distributed to the fetus.
Renal clearance of azilsartan is approximately 2.3 mL/min.
Metabolism / Metabolites
After azilsartan medoxomil is hydrolyzed into its active metabolite, azilsartan is metabolized to two primary metabolites, which are pharmacologically inactive. The major metabolite in plasma is metabolite M-II, which is formed via O-dealkylation mediated by CYP2C9. The minor metabolite is metabolite M-I, which is formed via decarboxylation mediated by CYP2C8 and CYP2B6. MII has approximately 50% systemic exposure of azilsartan, and MI has less than 1% systemic exposure of azilsartan.
Biological Half-Life
The elimination half-life of azilsartan is approximately 11 hours.
Toxicity/Toxicokinetics
Protein Binding
Azilsartan is >99% bound to human plasma proteins, mainly serum albumin. Protein binding is constant at azilsartan plasma concentrations well above the range achieved with recommended doses.
References
J Pharmacol Exp Ther.2011 Mar;336(3):801-8;Am J Hypertens.2007 May;20(5):579-86.
Additional Infomation
Pharmacodynamics
Pharmacodynamic effects of azilsartan medoxomil are mediated by its active metabolite, azilsartan. Azilsartan inhibits the pressor effects of an angiotensin II infusion in a dose-related manner. At a single 32 mg dose, azilsartan inhibited the maximal pressor effect by approximately 90% at peak plasma concentrations and by 60% at 24 hours after administration. In healthy subjects receiving single and repeated doses of azilsartan medoxomil, plasma angiotensin I and II concentrations and plasma renin activity increased, while plasma aldosterone concentrations decreased. Like other ARBs, azilsartan causes dose-dependent decrease in peripheral resistance and decreases smooth muscle vascular tone. As azilsartan blocks the angiotensin II receptor, the negative regulatory feedback of angiotensin II on renin secretion is inhibited; however, the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the blood pressure-lowering effect of azilsartan. Blood pressure-lowering effects of antihypertensive agents can be reduced in patients of African descent. However, there are no recommended dosage adjustment of azilsartan on the basis of a patient’s sex, race, or degree of renal or hepatic impairment. Azilsartan medoxomil has negligible effects on serum potassium or sodium levels. Azilsartan does not affect the biosynthesis of angiotensin II nor bradykinin levels. It also does not bind to any ion channels that are involved in cardiovascular regulation.
These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C30H24N4O8
Molecular Weight
568.53
Exact Mass
568.159
Elemental Analysis
C, 63.38; H, 4.26; N, 9.85; O, 22.51
CAS #
863031-21-4
Related CAS #
Azilsartan;147403-03-0;Azilsartan-d5;1346599-45-8;Azilsartan medoxomil monopotassium;863031-24-7
PubChem CID
135409642
Appearance
Solid powder
Density
1.5±0.1 g/cm3
Boiling Point
748.0±70.0 °C at 760 mmHg
Flash Point
406.2±35.7 °C
Vapour Pressure
0.0±2.5 mmHg at 25°C
Index of Refraction
1.680
LogP
5.73
Hydrogen Bond Donor Count
1
Hydrogen Bond Acceptor Count
10
Rotatable Bond Count
10
Heavy Atom Count
42
Complexity
1100
Defined Atom Stereocenter Count
0
SMILES
O=C1OC(COC(C2C3=C(N=C(N3CC3C=CC(C4C(C5NC(=O)ON=5)=CC=CC=4)=CC=3)OCC)C=CC=2)=O)=C(C)O1
InChi Key
QJFSABGVXDWMIW-UHFFFAOYSA-N
InChi Code
InChI=1S/C30H24N4O8/c1-3-38-28-31-23-10-6-9-22(27(35)39-16-24-17(2)40-30(37)41-24)25(23)34(28)15-18-11-13-19(14-12-18)20-7-4-5-8-21(20)26-32-29(36)42-33-26/h4-14H,3,15-16H2,1-2H3,(H,32,33,36)
Chemical Name
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-((2-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate
Synonyms
TAK-491; TAK 491; TAK491; Azilsartan medoxomil; Azilsartan medoxomil potassium; trade name: Edarbi. Ipreziv.
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: 114 mg/mL (200.5 mM)
Water:<1 mg/mL
Ethanol:<1 mg/mL
Solubility (In Vivo)
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.66 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 20.8 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: ≥ 2.08 mg/mL (3.66 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.7589 mL 8.7946 mL 17.5892 mL
5 mM 0.3518 mL 1.7589 mL 3.5178 mL
10 mM 0.1759 mL 0.8795 mL 1.7589 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.

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Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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In vivo Formulation Calculator (Clear solution)
Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)
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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.
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