Azilsartan medoxomil

Identification

Name
Azilsartan medoxomil
Accession Number
DB08822  (DB05358)
Type
Small Molecule
Groups
Approved, Investigational
Description

Azilsartan medoxomil is an angiotensin II receptor antagonist indicated for the treatment of mild to moderate essential hypertension. Azilsartan medoxomil is a prodrug of Azilsartan marketed as "Edarbi" by Takeda. Azilsartan medoxomil has so far been shown to be superior to olmesartan and valsartan in lowering blood pressure.

Structure
Thumb
Synonyms
  • Azilsartan
  • Azilsartan kamedoxomil
  • Azilsartan médoxomil
  • Azilsartán medoxomilo
  • Azilsartanum medoxomilum
External IDs
TAK 491 / TAK-491 / TAK-536
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
EdarbiTablet80 mg/1OralTakeda2011-02-252018-02-01Us
EdarbiTablet40 mgOralValeant Canada Lp Valeant Canada S.E.C.2012-11-08Not applicableCanada
EdarbiTablet80 mg/1OralArbor Pharmaceuticals2013-02-01Not applicableUs
EdarbiTablet40 mg/1OralTakeda2011-02-252018-02-01Us
EdarbiTablet40 mg/1OralArbor Pharmaceuticals2013-02-01Not applicableUs
EdarbiTablet80 mgOralValeant Canada Lp Valeant Canada S.E.C.2012-11-08Not applicableCanada
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
EdarbyclorAzilsartan medoxomil (40 mg/1) + Chlorthalidone (12.5 mg/1)TabletOralTakeda2011-12-232018-05-01Us
EdarbyclorAzilsartan medoxomil (40 mg) + Chlorthalidone (12.5 mg)TabletOralValeant Canada Lp Valeant Canada S.E.C.2013-03-21Not applicableCanada
EdarbyclorAzilsartan medoxomil (80 mg/1) + Chlorthalidone (12.5 mg/1)TabletOralTakeda Pharmaceuticals America, Inc.2011-12-232011-12-14Us
EdarbyclorAzilsartan medoxomil (40 mg/1) + Chlorthalidone (12.5 mg/1)TabletOralArbor Pharmaceuticals2013-02-01Not applicableUs
EdarbyclorAzilsartan medoxomil (80 mg) + Chlorthalidone (12.5 mg)TabletOralValeant Canada Lp Valeant Canada S.E.C.2013-03-21Not applicableCanada
EdarbyclorAzilsartan medoxomil (20 mg/1) + Chlorthalidone (12.5 mg/1)TabletOralTakeda Pharmaceuticals America, Inc.2011-12-232011-12-14Us
EdarbyclorAzilsartan medoxomil (40 mg/1) + Chlorthalidone (25 mg/1)TabletOralTakeda2011-12-232018-05-01Us
EdarbyclorAzilsartan medoxomil (40 mg) + Chlorthalidone (25 mg)TabletOralValeant Canada Lp Valeant Canada S.E.C.2013-03-21Not applicableCanada
EdarbyclorAzilsartan medoxomil (40 mg/1) + Chlorthalidone (25 mg/1)TabletOralArbor Pharmaceuticals2013-02-01Not applicableUs
Categories
UNII
LL0G25K7I2
CAS number
863031-21-4
Weight
Average: 568.5336
Monoisotopic: 568.159413764
Chemical Formula
C30H24N4O8
InChI Key
QJFSABGVXDWMIW-UHFFFAOYSA-N
InChI
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)
IUPAC Name
(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl 2-ethoxy-1-({4-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]phenyl}methyl)-1H-1,3-benzodiazole-7-carboxylate
SMILES
CCOC1=NC2=C(N1CC1=CC=C(C=C1)C1=CC=CC=C1C1=NOC(=O)N1)C(=CC=C2)C(=O)OCC1=C(C)OC(=O)O1

Pharmacology

Indication

Treatment of hypertension (alone or as an adjunct).

Associated Conditions
Pharmacodynamics

Azilsartan medoxomil decreases the pressor effect of angiotensin II. In response, angiotensin I, angiotensin II, and renin are increased while aldosterone is decreased.

Mechanism of action

Azilsartan medoxomil blocks the angiotensin II type 1 receptor preventing angiotensin II from binding and causing vasoconstriction. Azilsartan's ability to remain tightly bound to AT1 receptors for very long periods after drug washout is among its most unusual features.

TargetActionsOrganism
AType-1 angiotensin II receptor
antagonist
Human
Absorption

Azilsartan medoxomil is hydrolyzed to the active metabolite azilsartan in the GI tract. The presence of food does not affect oral absorption of azilsartan medoxomil, and the bioavailability is 60% for azilsartan. Maximum plasma concentrations are reached in 1.5 to 3 hours.

Volume of distribution

Azilsartan medoxomil has a Vd of 16L.

Protein binding

Azilsartan medoxomil is 99% plasma protein bound.

Metabolism

Azilsartan is metabolized by CYP2C9. CYP2C9 carries out decarboxylation of azilsartan to M-I, and O-dealkylation of azilsartan to M-II. Both M-I and M-II have no pharmacologic activity.

Route of elimination

Renal clearance is 2.3 L/minute.

Half life

The half-life is 11 hours, and it takes about 5 days to reach steady state concentrations.

Clearance

Fecal elimination accounts for 55%, urine excretion 42%, and unchanged drug 15%.

Toxicity

Hypotension and diarrhea are most common.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcebutololThe risk or severity of hyperkalemia can be increased when Acebutolol is combined with Azilsartan medoxomil.
AceclofenacThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Azilsartan medoxomil is combined with Aceclofenac.
AcemetacinThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Azilsartan medoxomil is combined with Acemetacin.
Acetylsalicylic acidThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Azilsartan medoxomil is combined with Acetylsalicylic acid.
AgmatineThe risk or severity of hyperkalemia can be increased when Azilsartan medoxomil is combined with Agmatine.
AlclofenacThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Azilsartan medoxomil is combined with Alclofenac.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Azilsartan medoxomil.
AliskirenThe risk or severity of hyperkalemia can be increased when Aliskiren is combined with Azilsartan medoxomil.
AlminoprofenThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Azilsartan medoxomil is combined with Alminoprofen.
AlogliptinThe risk or severity of angioedema can be increased when Alogliptin is combined with Azilsartan medoxomil.
Food Interactions
  • Food does not affect absorption or bioavailibity.
  • Nutrition/Herbal interaction

References

Synthesis Reference

Kohara Y, Kubo K, Imamiya E, Wada T, Inada Y, Naka T: Synthesis and angiotensin II receptor antagonistic activities of benzimidazole derivatives bearing acidic heterocycles as novel tetrazole bioisosteres. J Med Chem. 1996 Dec 20;39(26):5228-35.

General References
  1. Jones JD, Jackson SH, Agboton C, Martin TS: Azilsartan Medoxomil (Edarbi): The Eighth Angiotensin II Receptor Blocker. P T. 2011 Oct;36(10):634-40. [PubMed:22346296]
  2. Lanier G, Sankholkar K, Aronow WS: Azilsartan, aliskiren, and combination antihypertensives utilizing renin-angiotensin-aldosterone system antagonists. Am J Ther. 2014 Sep-Oct;21(5):419-35. doi: 10.1097/MJT.0b013e31824a0ed7. [PubMed:22975662]
  3. Kurtz TW, Kajiya T: Differential pharmacology and benefit/risk of azilsartan compared to other sartans. Vasc Health Risk Manag. 2012;8:133-43. doi: 10.2147/VHRM.S22595. Epub 2012 Feb 28. [PubMed:22399858]
External Links
KEGG Drug
D08865
PubChem Compound
11238823
PubChem Substance
175427104
ChemSpider
9413866
ChEBI
68845
ChEMBL
CHEMBL2028661
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Azilsartan
ATC Codes
C09CA09 — Azilsartan medoxomilC09DA09 — Azilsartan medoxomil and diuretics
AHFS Codes
  • 24:32.08 — Angiotensin Ii Receptor Antagonists
FDA label
Download (381 KB)
MSDS
Download (34.9 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceBioequivalence of Two Azilsartan Formulations1
1CompletedOtherHealthy Volunteers1
1CompletedTreatmentHigh Blood Pressure (Hypertension)1
1CompletedTreatmentJapanese Healthy Adult Male Participants1
1CompletedTreatmentJapanese Healthy Adult Males1
1RecruitingTreatmentHealthy Adult Male Participants1
1TerminatedNot AvailableHigh Blood Pressure (Hypertension)1
2CompletedTreatmentDiabetes Mellitus (DM)1
2CompletedTreatmentHigh Blood Pressure (Hypertension)2
2CompletedTreatmentHypertension,Essential1
2, 3Unknown StatusTreatmentBMI >30 kg/m2 / High Blood Pressure (Hypertension) / Type 2 Diabetes Mellitus1
3Active Not RecruitingTreatmentPediatric Hypertension1
3CompletedTreatmentHigh Blood Pressure (Hypertension)11
3CompletedTreatmentHigh Blood Pressure (Hypertension) / Safety and Efficacy og Azilsartan in Chinese Hypertension Patients1
3CompletedTreatmentHypertension,Essential6
3CompletedTreatmentPediatric Hypertension1
3CompletedTreatmentSafety1
3RecruitingTreatmentHigh Blood Pressure (Hypertension)1
3TerminatedTreatmentDiabetes Mellitus (DM) / High Blood Pressure (Hypertension)1
3TerminatedTreatmentType 2 Diabetes Mellitus2
3Unknown StatusTreatmentHypertension,Essential1
4CompletedTreatmentEssential Hypertension Complicated by Type 2 Diabetes Mellitus1
4CompletedTreatmentHigh Blood Pressure (Hypertension)1
4CompletedTreatmentHypertension,Essential / Type 2 Diabetes Mellitus1
4WithdrawnTreatmentEssential Hypertension With Stable Angina and Dyslipidemia1
Not AvailableCompletedNot AvailableHigh Blood Pressure (Hypertension)4
Not AvailableCompletedTreatmentHigh Blood Pressure (Hypertension)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral40 mg
TabletOral40 mg/1
TabletOral80 mg/1
TabletOral80 mg
TabletOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US9169238No2015-10-272030-02-25Us
US7572920No2009-08-112025-01-07Us
US9066936No2015-06-302028-03-26Us
US7157584No2007-01-022025-05-22Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)212-214Not Available
water solubilitypractically insolubleNot Available
pKa6.1Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00703 mg/mLALOGPS
logP4.94ALOGPS
logP6.03ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)9.21ChemAxon
pKa (Strongest Basic)1.75ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area139.57 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity149.52 m3·mol-1ChemAxon
Polarizability57.73 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.915
Caco-2 permeable-0.5843
P-glycoprotein substrateSubstrate0.5619
P-glycoprotein inhibitor INon-inhibitor0.5061
P-glycoprotein inhibitor IINon-inhibitor0.7217
Renal organic cation transporterNon-inhibitor0.8851
CYP450 2C9 substrateNon-substrate0.834
CYP450 2D6 substrateNon-substrate0.8338
CYP450 3A4 substrateSubstrate0.5128
CYP450 1A2 substrateNon-inhibitor0.7445
CYP450 2C9 inhibitorInhibitor0.5531
CYP450 2D6 inhibitorNon-inhibitor0.8779
CYP450 2C19 inhibitorInhibitor0.5915
CYP450 3A4 inhibitorInhibitor0.8507
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.594
Ames testNon AMES toxic0.5227
CarcinogenicityNon-carcinogens0.7059
BiodegradationNot ready biodegradable0.9962
Rat acute toxicity2.5320 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8853
hERG inhibition (predictor II)Non-inhibitor0.6952
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as biphenyls and derivatives. These are organic compounds containing to benzene rings linked together by a C-C bond.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Biphenyls and derivatives
Direct Parent
Biphenyls and derivatives
Alternative Parents
Phenyloxadiazoles / Benzimidazoles / Alkyl aryl ethers / N-substituted imidazoles / Carbonic acid diesters / Vinylogous amides / Heteroaromatic compounds / Carboxylic acid esters / Oxacyclic compounds / Monocarboxylic acids and derivatives
show 5 more
Substituents
Biphenyl / Phenyl-1,2,4-oxadiazole / Benzimidazole / Alkyl aryl ether / Carbonic acid diester / N-substituted imidazole / 1,2,4-oxadiazole / Azole / Heteroaromatic compound / Imidazole
show 17 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
aromatic ether, carboxylic ester, dioxolane, cyclic carbonate ester, benzimidazoles, 1,2,4-oxadiazole (CHEBI:68845)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Protein heterodimerization activity
Specific Function
Receptor for angiotensin II. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.
Gene Name
AGTR1
Uniprot ID
P30556
Uniprot Name
Type-1 angiotensin II receptor
Molecular Weight
41060.53 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. Miura S, Matsuo Y, Nakayama A, Tomita S, Suematsu Y, Saku K: Ability of the new AT1 receptor blocker azilsartan to block angiotensin II-induced AT1 receptor activation after wash-out. J Renin Angiotensin Aldosterone Syst. 2014 Mar;15(1):7-12. doi: 10.1177/1470320313482170. Epub 2013 Apr 5. [PubMed:23563275]

Drug created on December 21, 2012 10:01 / Updated on November 18, 2018 13:32