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Details

Stereochemistry RACEMIC
Molecular Formula C36H34N6O8
Molecular Weight 678.6906
Optical Activity ( + / - )
Defined Stereocenters 0 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of AZILSARTAN MEPIXETIL

SMILES

CCOC1=NC2=CC=CC(C(=O)OC(C)OC(=O)OCC3=NC(C)=C(C)N=C3C)=C2N1CC4=CC=C(C=C4)C5=C(C=CC=C5)C6=NOC(=O)N6

InChI

InChIKey=JXSDNNVNQNYJSP-UHFFFAOYSA-N
InChI=1S/C36H34N6O8/c1-6-46-34-39-29-13-9-12-28(33(43)48-23(5)49-36(45)47-19-30-22(4)37-20(2)21(3)38-30)31(29)42(34)18-24-14-16-25(17-15-24)26-10-7-8-11-27(26)32-40-35(44)50-41-32/h7-17,23H,6,18-19H2,1-5H3,(H,40,41,44)

HIDE SMILES / InChI

Molecular Formula C36H34N6O8
Molecular Weight 678.6906
Charge 0
Count
Stereochemistry RACEMIC
Additional Stereochemistry No
Defined Stereocenters 0 / 1
E/Z Centers 0
Optical Activity ( + / - )

Description
Curator's Comment: description was created based on several sources, including https://www.takeda.com/news/2011/20110224_3831.html; https://www.ncbi.nlm.nih.gov/pubmed/?term=22346296

Azilsartan medoxomil (trade name Edarb) is an angiotensin II receptor blocker (ARB) that lowers blood pressure by blocking the action of angiotensin II, a vasopressor hormone. It is indicated for the treatment of hypertension to lower blood pressure which reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. Azilsartan medoxomil may be used either alone or in combination with other antihypertensive agents such as chlorthalidone (CLD). As an ARB, azilsartan medoxomil selectively inhibits angiotensin II from binding to the angiotensin II type-1 receptor (AT1). This receptor inhibition provides the antihypertensive activity of azilsartan medoxomil because it blocks the pressor effects of angiotensin II. Azilsartan medoxomil is a prodrug of azilsartan. It is hydrolyzed to the active moiety, azilsartan, in the gastrointestinal (GI) tract during the absorption phase. Azilsartan medoxomil, in combination with the thiazide-like diuretic chlorthalidone, was more effective in lowering systolic BP than azilsartan plus HCTZ.

CNS Activity

Curator's Comment: In rats, minimal azilsartan-associated radioactivity crossed the blood-brain barrier.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Target ID: P30556
Gene ID: 185.0
Gene Symbol: AGTR1
Target Organism: Homo sapiens (Human)
0.62 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
EDARBI

Approved Use

Indicated for the treatment of hypertension to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. Edarbi may be used either alone or in combination with other antihypertensive agents.

Launch Date

1.29859204E12
Primary
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
5355.71 ng/mL
80 mg single, oral
dose: 80 mg
route of administration: Oral
experiment type: SINGLE
co-administered: Chlorthalidone
AZILSARTAN plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
141.3 ng/mL
10 mg single, oral
dose: 10 mg
route of administration: oral
experiment type: single
co-administered:
AZILSARTAN METABOLITE M-I plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status: Fed
191.3 ng/mL
5 mg single, oral
dose: 5 mg
route of administration: oral
experiment type: single
co-administered:
AZILSARTAN METABOLITE M-I plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status: Fed
227.7 ng/mL
5 mg single, oral
dose: 5 mg
route of administration: oral
experiment type: single
co-administered:
AZILSARTAN METABOLITE M-II plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status: Fed
179.3 ng/mL
10 mg single, oral
dose: 10 mg
route of administration: oral
experiment type: single
co-administered:
AZILSARTAN METABOLITE M-II plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status: Fed
888.3 ng/mL
5 mg single, oral
dose: 5 mg
route of administration: oral
experiment type: single
co-administered:
AZILSARTAN plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status: Fed
831.3 ng/mL
10 mg single, oral
dose: 10 mg
route of administration: oral
experiment type: single
co-administered:
AZILSARTAN plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status: Fed
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
46688.2 ng × h/mL
80 mg single, oral
dose: 80 mg
route of administration: Oral
experiment type: SINGLE
co-administered: Chlorthalidone
AZILSARTAN plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
1420.5 ng*h/mL
10 mg single, oral
dose: 10 mg
route of administration: oral
experiment type: single
co-administered:
AZILSARTAN METABOLITE M-I plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status: Fed
1592.7 ng*h/mL
5 mg single, oral
dose: 5 mg
route of administration: oral
experiment type: single
co-administered:
AZILSARTAN METABOLITE M-I plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status: Fed
1986.5 ng*h/mL
5 mg single, oral
dose: 5 mg
route of administration: oral
experiment type: single
co-administered:
AZILSARTAN METABOLITE M-II plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status: Fed
3526 ng*h/mL
10 mg single, oral
dose: 10 mg
route of administration: oral
experiment type: single
co-administered:
AZILSARTAN METABOLITE M-II plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status: Fed
6350.3 ng*h/mL
5 mg single, oral
dose: 5 mg
route of administration: oral
experiment type: single
co-administered:
AZILSARTAN plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status: Fed
6871.7 ng*h/mL
10 mg single, oral
dose: 10 mg
route of administration: oral
experiment type: single
co-administered:
AZILSARTAN plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status: Fed
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
12.1 h
80 mg single, oral
dose: 80 mg
route of administration: Oral
experiment type: SINGLE
co-administered: Chlorthalidone
AZILSARTAN plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
1%
80 mg 1 times / day unknown, oral
dose: 80 mg
route of administration: Oral
experiment type: UNKNOWN
co-administered:
AZILSARTAN plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
80 mg 1 times / day multiple, oral (max)
Recommended
Dose: 80 mg, 1 times / day
Route: oral
Route: multiple
Dose: 80 mg, 1 times / day
Sources: Page: p.187
unhealthy, 50.4+/-10.2
n = 179
Health Status: unhealthy
Condition: Hypertension
Age Group: 50.4+/-10.2
Sex: M+F
Population Size: 179
Sources: Page: p.187
Disc. AE: Dizziness, Fatigue...
AEs leading to
discontinuation/dose reduction:
Dizziness (3.35%)
Fatigue (2.79%)
Sources: Page: p.187
320 mg 1 times / day multiple, oral
Overdose
Dose: 320 mg, 1 times / day
Route: oral
Route: multiple
Dose: 320 mg, 1 times / day
Sources: Page: p.6
healthy
80 mg 1 times / day multiple, oral (max)
Recommended
Dose: 80 mg, 1 times / day
Route: oral
Route: multiple
Dose: 80 mg, 1 times / day
Sources: Page: p.4
unhealthy
n = 2146
Health Status: unhealthy
Condition: Hypertension
Population Size: 2146
Sources: Page: p.4
Disc. AE: Hypotension orthostatic...
AEs leading to
discontinuation/dose reduction:
Hypotension orthostatic (0.4%)
Sources: Page: p.4
AEs

AEs

AESignificanceDosePopulation
Fatigue 2.79%
Disc. AE
80 mg 1 times / day multiple, oral (max)
Recommended
Dose: 80 mg, 1 times / day
Route: oral
Route: multiple
Dose: 80 mg, 1 times / day
Sources: Page: p.187
unhealthy, 50.4+/-10.2
n = 179
Health Status: unhealthy
Condition: Hypertension
Age Group: 50.4+/-10.2
Sex: M+F
Population Size: 179
Sources: Page: p.187
Dizziness 3.35%
Disc. AE
80 mg 1 times / day multiple, oral (max)
Recommended
Dose: 80 mg, 1 times / day
Route: oral
Route: multiple
Dose: 80 mg, 1 times / day
Sources: Page: p.187
unhealthy, 50.4+/-10.2
n = 179
Health Status: unhealthy
Condition: Hypertension
Age Group: 50.4+/-10.2
Sex: M+F
Population Size: 179
Sources: Page: p.187
Hypotension orthostatic 0.4%
Disc. AE
80 mg 1 times / day multiple, oral (max)
Recommended
Dose: 80 mg, 1 times / day
Route: oral
Route: multiple
Dose: 80 mg, 1 times / day
Sources: Page: p.4
unhealthy
n = 2146
Health Status: unhealthy
Condition: Hypertension
Population Size: 2146
Sources: Page: p.4
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no [IC50 >100 uM]
no [IC50 >100 uM]
no [IC50 >100 uM]
no [IC50 >100 uM]
no [IC50 >100 uM]
no [IC50 >100 uM]
no (co-administration study)
Comment: Human liver microsomes (Phenacetin O-deethylation), Maximum inhibition = 5.1%; Coadministration of Azilsartan medoxomil (80 mg QD for 6 days) did not significantly affect Caffeine (200 mg QD on Day 6, CYP1A2 substrate) AUC and Cmax.
Page: 9, 46-47, (ClinPharm) 15, 17-18, 58-59
no [IC50 >100 uM]
no (co-administration study)
Comment: Human liver microsomes (Paclitaxel 6a-hydroxylation), Maximum inhibition = 10.1%; Pioglitazone does not affect systemic exposure to Azilzartan, and systemic exposure to pioglitazone is not affected by Azilzartan.
Page: 9, 46-47, (ClinPharm) 15, 17-18, 77-78
no [IC50 >100 uM]
no (co-administration study)
Comment: Human liver microsomes (Diclofenac 4'-hydroxylation), Inhibited CYP2C9 activities at 30 (14.4%) and 100 mcM (37.9%); Human CYP expressing microsomes derived from B-lymphoblastoid cells (tolbutamide hydroxylation); Coadministration of Azilsartan medoxomil (80 mg QD for 6 days) did not significantly affect Tolbutamide (500 mg QD on Day 6, CYP2C9 substrate) AUC and Cmax.; Azilzartan dose not affect the pharmacokinetics and pharmacodynamics of warfarin and is not expected to significantly affect systemic exposure to other CYP 2C9 substartes.
Page: 9, 46-47, (ClinPharm) 15, 17-18, 58-59, 66-68
no [IC50 >100 uM]
no (co-administration study)
Comment: Human liver microsomes (Bufuralol 1'-hydroxylation), Maximum inhibition = 5.1%; Coadministration of Azilsartan medoxomil (80 mg QD for 6 days) did not significantly affect Dextromethorphan (30 mg QD on Day 6, CYP2D6 substrate) AUC and Cmax.
Page: 9, 46-47, (ClinPharm) 15, 17-18, 58-59
no [IC50 >100 uM]
no (co-administration study)
Comment: Human liver microsomes (Midazolam 17-hydroxylation, Testosterone 6b-hydroxylation), Maximum inhibition = /<0%; Coadministration of Azilsartan medoxomil(80 mg QD for 6 days) did not significantly affect Midazolam (4 mg QD on Day 6, CYP3A4 substrate) AUC and Cmax.; Amlodipine does not affect systemic exposure to Azilzartan, and systemic exposure to amlodipine is not affected by Azilzartan.
Page: 9, 46-47, (ClinPharm) 15, 17-18, 58-59, 73-74
unlikely
unlikely
weak (co-administration study)
Comment: Caco-2 cells (After incubation at 37°C for 2 hours with Azilzartan (at 0, 20, 100, and 500 μmol/L), efflux ratios of digoxin were 6.4, 7.0, 6.6, and 7.23. These results show that Azilsartan had no inhibitory effect on P-gp-mediated efflux activity.; Coadministration of Azilsartan medoxomil (80 mg QD for 6 days) did not significantly affect Fexofenadine (60 mg QD on Day 6, P-gp substrate) AUC and Cmax.; Coadminitration of Azilzartan (80 mg QD for 10 days) increased Digoxin (200 mcg QD for 10 days) AUC0-tau by 2.87% and decreased Cmax by 5.71%.
Page: 35, (ClinPharm) 22-23, 58-59, 62-63
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
inconclusive
major
yes (co-administration study)
Comment: O-dealkylation to form Azilsartan M-II primarily by CYP2C9, Incubation of 14C-AZILSARTAN with microsomes from baculovirus-infected insect cellsexpressuing human CYP isoforms (elimination and formation (M-1 & M-II) rate); Human liver microsomes (16 donors); Clearance of Azilzartan (40 mg QD on Days 1 & 10) is reduced when co-administered with fluconazole (200 mg QD on Days 4-10), a CYP 2C9 inhibitor. This is evident from the ~ 40% increase in AUC, but only ~ 14% increase in Cmax. However, this is not of clinical significance given the flat D-R relationship for Azilzartan and the absence of serious adverse events.; Systemic exposure to glyburide (5 mg QD on DAy 8) is not affected by Azilzartan (40 mg QD for 8 days).
Page: 9, 45, (ClinPharm) 14, 64-65, 69-70
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes (co-administration study)
Comment: Incubation of 14C-AZILSARTAN with microsomes from baculovirus-infected insect cellsexpressuing human CYP isoforms (elimination and formation (M-1 & M-II) rate); Human liver microsomes (16 donors); When co-administered with ketoconazole (400 mg QD on Days 4-10), Cmax of Azilzartan (40 mg QD on Day 1 & 10) decreased by ~ 30% and AUC by ~ 20%. However, the reason for this is not apparent.
Page: 9, 45, (ClinPharm) 14, 64-65
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
TAK-536, a new AT1 receptor blocker, improves glucose intolerance and adipocyte differentiation.
2007 May
A systematic comparison of the properties of clinically used angiotensin II type 1 receptor antagonists.
2013 Apr
Azilsartan, aliskiren, and combination antihypertensives utilizing renin-angiotensin-aldosterone system antagonists.
2014 Sep-Oct
Patents

Sample Use Guides

For 4 weeks during the run-in period, one tablet of TAK-536CCB (as TAK-536/ amlodipine, 20 mg/5 mg, respectively) will be orally administered once daily, before or after breakfast. For 48 weeks during 52 weeks of the treatment period, one tablet of TAK-536TCH (as TAK-536/ amlodipine/amlodipine, 20 mg/5 mg/12.5 mg, respectively) will be orally administered once daily, before or after breakfast. For the remaining 4 weeks of the treatment period, one tablet each of TAK-536CCB and HCTZ 12.5 mg will be orally administered once daily, before or after breakfast.
Route of Administration: Oral
In Vitro Use Guide
Unknown
Substance Class Chemical
Created
by admin
on Fri Jul 07 00:23:15 UTC 2023
Edited
by admin
on Fri Jul 07 00:23:15 UTC 2023
Record UNII
C2GK4G74Y7
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
AZILSARTAN MEPIXETIL
INN  
Official Name English
QR-01019
Code English
azilsartan mepixetil [INN]
Common Name English
1-((((3,5,6-TRIMETHYL-2-PYRAZINYL)METHOXY)CARBONYL)OXY)ETHYL 1-((2'-(2,5-DIHYDRO-5-OXO-1,2,4-OXADIAZOL-3-YL)(1,1'-BIPHENYL)-4-YL)METHYL)-2-ETHOXY-1H-BENZIMIDAZOLE-7-CARBOXYLATE
Systematic Name English
1H-BENZIMIDAZOLE-7-CARBOXYLIC ACID, 1-((2'-(2,5-DIHYDRO-5-OXO-1,2,4-OXADIAZOL-3-YL)(1,1'-BIPHENYL)-4-YL)METHYL)-2-ETHOXY-, 1-((((3,5,6-TRIMETHYL-2-PYRAZINYL)METHOXY)CARBONYL)OXY)ETHYL ESTER
Systematic Name English
Code System Code Type Description
PUBCHEM
137091385
Created by admin on Fri Jul 07 00:23:16 UTC 2023 , Edited by admin on Fri Jul 07 00:23:16 UTC 2023
PRIMARY
SMS_ID
300000042068
Created by admin on Fri Jul 07 00:23:16 UTC 2023 , Edited by admin on Fri Jul 07 00:23:16 UTC 2023
PRIMARY
INN
12110
Created by admin on Fri Jul 07 00:23:16 UTC 2023 , Edited by admin on Fri Jul 07 00:23:16 UTC 2023
PRIMARY
NCI_THESAURUS
C188556
Created by admin on Fri Jul 07 00:23:16 UTC 2023 , Edited by admin on Fri Jul 07 00:23:16 UTC 2023
PRIMARY
CAS
1596357-16-2
Created by admin on Fri Jul 07 00:23:16 UTC 2023 , Edited by admin on Fri Jul 07 00:23:16 UTC 2023
PRIMARY
FDA UNII
C2GK4G74Y7
Created by admin on Fri Jul 07 00:23:16 UTC 2023 , Edited by admin on Fri Jul 07 00:23:16 UTC 2023
PRIMARY
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