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Identification
NameAzilsartan medoxomil
Accession NumberDB08822
TypeSmall Molecule
GroupsApproved
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 medoxomilo
Azilsartanum medoxomilum
Edarbi
External Identifiers
  • TAK-491
  • TAK-536
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Edarbitablet40 mg/1oralTakeda Pharmaceuticals America, Inc.2011-02-25Not applicableUs
Edarbitablet80 mg/1oralArbor Pharmaceuticals2013-02-01Not applicableUs
Edarbitablet40 mg/1oralArbor Pharmaceuticals2013-02-01Not applicableUs
Edarbitablet80 mgoralValeant Canada Lp Valeant Canada S.E.C.2012-11-08Not applicableCanada
Edarbitablet40 mgoralValeant Canada Lp Valeant Canada S.E.C.2012-11-08Not applicableCanada
Edarbitablet80 mg/1oralTakeda Pharmaceuticals America, Inc.2011-02-25Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixtures
NameLabellerIngredients
EdarbyclorTakeda Pharmaceuticals America, Inc.
SaltsNot Available
Categories
UNIILL0G25K7I2
CAS number863031-21-4
WeightAverage: 568.5336
Monoisotopic: 568.159413764
Chemical FormulaC30H24N4O8
InChI KeyInChIKey=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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as tetracarboxylic acids and derivatives. These are carboxylic acids containing exactly four carboxyl groups.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassTetracarboxylic acids and derivatives
Direct ParentTetracarboxylic acids and derivatives
Alternative Parents
Substituents
  • Tetracarboxylic acid or derivatives
  • Biphenyl
  • Benzylether
  • Benzimidazole
  • Phenylmethylamine
  • Benzoyl
  • Alkyl aryl ether
  • Benzenoid
  • N-substituted imidazole
  • Carbonic acid diester
  • Monocyclic benzene moiety
  • Heteroaromatic compound
  • Vinylogous amide
  • Oxadiazole
  • Imidazole
  • Azole
  • 1,2,4-oxadiazole
  • Carboxylic acid ester
  • Oxacycle
  • Azacycle
  • Organoheterocyclic compound
  • Ether
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationTreatment of hypertension (alone or as an adjunct).
PharmacodynamicsAzilsartan medoxomil decreases the pressor effect of angiotensin II. In response, angiotensin I, angiotensin II, and renin are increased while aldosterone is decreased.
Mechanism of actionAzilsartan 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.
Related Articles
AbsorptionAzilsartan 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 bindingAzilsartan 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 eliminationRenal clearance is 2.3 L/minute.
Half lifeThe 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%.

ToxicityHypotension and diarrhea are most common.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tabletoral40 mg/1
Tabletoral40 mg
Tabletoral80 mg/1
Tabletoral80 mg
Tabletoral
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7157584 No2005-05-222025-05-22Us
US7572920 No2005-01-072025-01-07Us
US9066936 No2008-03-262028-03-26Us
US9169238 No2010-02-252030-02-25Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point212-214Not 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 FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
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
ATC CodesC09CA09C09DA09
AHFS Codes
  • 24:32.08
PDB EntriesNot Available
FDA labelDownload (381 KB)
MSDSDownload (34.9 KB)
Interactions
Drug Interactions
Drug
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Azilsartan medoxomil.
AlfuzosinAlfuzosin may increase the hypotensive activities of Azilsartan medoxomil.
AliskirenAliskiren may increase the hyperkalemic activities of Azilsartan medoxomil.
AmifostineAzilsartan medoxomil may increase the hypotensive activities of Amifostine.
ArdeparinArdeparin may increase the hyperkalemic activities of Azilsartan medoxomil.
BrimonidineBrimonidine may increase the antihypertensive activities of Azilsartan medoxomil.
ButabarbitalButabarbital may increase the hypotensive activities of Azilsartan medoxomil.
ButethalButethal may increase the hypotensive activities of Azilsartan medoxomil.
CanagliflozinCanagliflozin may increase the hyperkalemic activities of Azilsartan medoxomil.
CiprofloxacinAzilsartan medoxomil may increase the arrhythmogenic activities of Ciprofloxacin.
CyclosporineAzilsartan medoxomil may increase the hyperkalemic activities of Cyclosporine.
DapoxetineDapoxetine may increase the orthostatic hypotensive activities of Azilsartan medoxomil.
DiazoxideDiazoxide may increase the hypotensive activities of Azilsartan medoxomil.
DrospirenoneAzilsartan medoxomil may increase the hyperkalemic activities of Drospirenone.
DuloxetineAzilsartan medoxomil may increase the orthostatic hypotensive activities of Duloxetine.
EplerenoneEplerenone may increase the hyperkalemic activities of Azilsartan medoxomil.
HeparinHeparin may increase the hyperkalemic activities of Azilsartan medoxomil.
HeptabarbitalHeptabarbital may increase the hypotensive activities of Azilsartan medoxomil.
HexobarbitalHexobarbital may increase the hypotensive activities of Azilsartan medoxomil.
InfliximabThe risk or severity of adverse effects can be increased when Azilsartan medoxomil is combined with Infliximab.
LevodopaAzilsartan medoxomil may increase the orthostatic hypotensive activities of Levodopa.
LithiumThe serum concentration of Lithium can be increased when it is combined with Azilsartan medoxomil.
MethohexitalMethohexital may increase the hypotensive activities of Azilsartan medoxomil.
MethylphenidateMethylphenidate may decrease the antihypertensive activities of Azilsartan medoxomil.
MolsidomineMolsidomine may increase the hypotensive activities of Azilsartan medoxomil.
MoxonidineMoxonidine may increase the hypotensive activities of Azilsartan medoxomil.
NicorandilNicorandil may increase the hypotensive activities of Azilsartan medoxomil.
ObinutuzumabAzilsartan medoxomil may increase the hypotensive activities of Obinutuzumab.
PentobarbitalPentobarbital may increase the hypotensive activities of Azilsartan medoxomil.
PentoxifyllinePentoxifylline may increase the hypotensive activities of Azilsartan medoxomil.
PerindoprilThe risk or severity of adverse effects can be increased when Azilsartan medoxomil is combined with Perindopril.
PhenelzinePhenelzine may increase the orthostatic hypotensive activities of Azilsartan medoxomil.
PrimidonePrimidone may increase the hypotensive activities of Azilsartan medoxomil.
QuinineQuinine may increase the hypotensive activities of Azilsartan medoxomil.
RisperidoneAzilsartan medoxomil may increase the hypotensive activities of Risperidone.
RituximabAzilsartan medoxomil may increase the hypotensive activities of Rituximab.
SecobarbitalSecobarbital may increase the hypotensive activities of Azilsartan medoxomil.
TadalafilTadalafil may increase the antihypertensive activities of Azilsartan medoxomil.
TolvaptanTolvaptan may increase the hyperkalemic activities of Azilsartan medoxomil.
TranylcypromineTranylcypromine may increase the orthostatic hypotensive activities of Azilsartan medoxomil.
TreprostinilTreprostinil may increase the hypotensive activities of Azilsartan medoxomil.
TriamtereneAzilsartan medoxomil may increase the hyperkalemic activities of Triamterene.
TrimethoprimTrimethoprim may increase the hyperkalemic activities of Azilsartan medoxomil.
ValsartanThe risk or severity of adverse effects can be increased when Valsartan is combined with Azilsartan medoxomil.
VardenafilVardenafil may increase the antihypertensive activities of Azilsartan medoxomil.
YohimbineYohimbine may decrease the antihypertensive activities of Azilsartan medoxomil.
Food Interactions
  • Food does not affect absorption or bioavailibity.
  • Nutrition/Herbal interaction

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
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 ]
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Drug created on December 21, 2012 10:01 / Updated on May 24, 2016 02:08