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Identification
NameCandesartan
Accession NumberDB00796  (APRD00420)
TypeSmall Molecule
GroupsApproved
Description

Candesartan is an angiotensin-receptor blocker (ARB) that may be used alone or with other agents to treat hypertension. It is administered orally as the prodrug, candesartan cilexetil, which is rapidly converted to its active metabolite, candesartan, during absorption in the gastrointestinal tract. Candesartan lowers blood pressure by antagonizing the renin-angiotensin-aldosterone system (RAAS); it competes with angiotensin II for binding to the type-1 angiotensin II receptor (AT1) subtype and prevents the blood pressure increasing effects of angiotensin II. Unlike angiotensin-converting enzyme (ACE) inhibitors, ARBs do not have the adverse effect of dry cough. Candesartan may be used to treat hypertension, isolated systolic hypertension, left ventricular hypertrophy and diabetic nephropathy. It may also be used as an alternative agent for the treatment of heart failure, systolic dysfunction, myocardial infarction and coronary artery disease.

Structure
Thumb
Synonyms
SynonymLanguageCode
2-Ethoxy-1-(P-(O-1H-tetrazol-5-ylphenyl)benzyl)-7-benzimidazolecarboxylic acidNot AvailableNot Available
2-Ethoxy-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acidNot AvailableNot Available
2-Ethoxy-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4ethyl]}-1H-benzimidazole-7-carboxylic acidNot AvailableNot Available
BlopressNot AvailableNot Available
Candesartan cilexetilNot AvailableNot Available
CV-11974Not AvailableNot Available
SaltsNot Available
Brand names
NameCompany
AmiasEureco (Netherlands), Takeda (United Kingdom)
AtacandAstraZeneca
BlopressTakeda
Brand mixtures
Brand NameIngredients
Atacand PlusCandesartan Cilexetil + Hydrochlorothiazide
Categories
CAS number139481-59-7
WeightAverage: 440.454
Monoisotopic: 440.159688536
Chemical FormulaC24H20N6O3
InChI KeyHTQMVQVXFRQIKW-UHFFFAOYSA-N
InChI
InChI=1S/C24H20N6O3/c1-2-33-24-25-20-9-5-8-19(23(31)32)21(20)30(24)14-15-10-12-16(13-11-15)17-6-3-4-7-18(17)22-26-28-29-27-22/h3-13H,2,14H2,1H3,(H,31,32)(H,26,27,28,29)
IUPAC Name
2-ethoxy-1-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1H-1,3-benzodiazole-7-carboxylic acid
SMILES
CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC1=CC=C(C=C1)C1=CC=CC=C1C1=NNN=N1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassAzoles
SubclassTetrazoles
Direct parentBiphenyltetrazoles and Derivatives
Alternative parentsBiphenyls and Derivatives; Benzimidazoles; Benzoic Acids; Benzoyl Derivatives; Alkyl Aryl Ethers; N-substituted Imidazoles; Enolates; Carboxylic Acids; Polyamines
Substituentsbiphenyl; benzoic acid or derivative; benzimidazole; benzoic acid; benzoyl; alkyl aryl ether; n-substituted imidazole; benzene; imidazole; carboxylic acid derivative; carboxylic acid; ether; enolate; polyamine; organonitrogen compound; amine
Classification descriptionThis compound belongs to the biphenyltetrazoles and derivatives. These are organic compounds containing a biphenyl attached to a tetrazole. A carbon atom of the biphenyl moiety is boned to a carbon or the nitrogen atom of the tetrazole moiety.
Pharmacology
IndicationMay be used as a first line agent to treat uncomplicated hypertension, isolated systolic hypertension and left ventricular hypertrophy. May be used as a first line agent to delay progression of diabetic nephropathy. Candesartan may be also used as a second line agent in the treatment of congestive heart failure, systolic dysfunction, myocardial infarction and coronary artery disease in those intolerant of ACE inhibitors.
PharmacodynamicsCandesartan cilexetil is an ARB prodrug that is rapidly converted to candesartan, its active metabolite, during absorption from the gastrointestinal tract. Candesartan confers blood pressure lowering effects by antagonizing the hypertensive effects of angiotensin II via the RAAS. RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. Renin cleaves circulating angiotensinogen to angiotensin I, which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II increases blood pressure by increasing total peripheral resistance, increasing sodium and water reabsorption in the kidneys via aldosterone secretion, and altering cardiovascular structure. Angiotensin II binds to two receptors: type-1 angiotensin II receptor (AT1) and type-2 angiotensin II receptor (AT2). AT1 is a G-protein coupled receptor (GPCR) that mediates the vasoconstrictive and aldosterone-secreting effects of angiotensin II. Studies performed in recent years suggest that AT2 antagonizes AT1-mediated effects and directly affects long-term blood pressure control by inducing vasorelaxation and increasing urinary sodium excretion. Angiotensin receptor blockers (ARBs) are non-peptide competitive inhibitors of AT1. ARBs block the ability of angiotensin II to stimulate pressor and cell proliferative effects. Unlike ACE inhibitors, ARBs do not affect bradykinin-induced vasodilation. The overall effect of ARBs is a decrease in blood pressure.
Mechanism of actionCandesartan selectively blocks the binding of angiotensin II to AT1 in many tissues including vascular smooth muscle and the adrenal glands. This inhibits the AT1-mediated vasoconstrictive and aldosterone-secreting effects of angiotensin II and results in an overall decrease in blood pressure. Candesartan is greater than 10,000 times more selective for AT1 than AT2. Inhibition of aldosterone secretion may increase sodium and water excretion while decreasing potassium excretion.
AbsorptionFollowing administration of the candesartan cilexetil prodrug, the absolute bioavailability of candesartan was estimated to be 15%. Food with a high fat content has no affect on the bioavailability of candesartan from candesartan cilexetil.
Volume of distribution
  • 0.13 L/kg
Protein bindingCandesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells.
Metabolism

The prodrug candesartan cilexetil undergoes rapid and complete ester hydrolysis in the intestinal wall to form the active drug, candesartan. Elimination of candesartan is primarily as unchanged drug in the urine and, by the biliary route, in the feces. Minor hepatic metabolism of candesartan (<20%)occurs by O-deethylation via cytochrome P450 2C9 to form an inactive metabolite. Candesartan undergoes N-glucuronidation in the tetrazole ring by uridine diphosphate glucuronosyltransferase 1A3 (UGT1A3). O-glucuronidation may also occur. 75% of candesartan is excreted as unchanged drug in urine and feces.

SubstrateEnzymesProduct
Candesartan
O-Deethylated candesartanDetails
Candesartan
Candesartan N2-glucuronideDetails
Candesartan
Candesartan O-glucuronideDetails
Route of eliminationWhen candesartan is administered orally, about 26% of the dose is excreted unchanged in urine. Candesartan is mainly excreted unchanged in urine and feces (via bile).
Half lifeApproximately 9 hours.
Clearance
  • 0.37 mL/min/kg
ToxicityNo lethality was observed in acute toxicity studies in mice, rats and dogs given single oral doses of up to 2000 mg/kg of candesartan cilexetil or in rats given single oral doses of up to 2000 mg/kg of candesartan cilexetil in combination with 1000 mg/kg of hydrochlorothiazide. In mice given single oral doses of the primary metabolite, candesartan, the minimum lethal dose was greater than 1000 mg/kg but less than 2000 mg/kg.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Candesartan Action PathwayDrug actionSMP00158
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.8717
Caco-2 permeable - 0.6208
P-glycoprotein substrate Substrate 0.5186
P-glycoprotein inhibitor I Non-inhibitor 0.848
P-glycoprotein inhibitor II Non-inhibitor 0.9115
Renal organic cation transporter Non-inhibitor 0.8266
CYP450 2C9 substrate Non-substrate 0.7397
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Non-substrate 0.6504
CYP450 1A2 substrate Inhibitor 0.5594
CYP450 2C9 substrate Inhibitor 0.5195
CYP450 2D6 substrate Non-inhibitor 0.889
CYP450 2C19 substrate Inhibitor 0.5151
CYP450 3A4 substrate Inhibitor 0.7392
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7895
Ames test AMES toxic 0.556
Carcinogenicity Non-carcinogens 0.7561
Biodegradation Not ready biodegradable 0.9972
Rat acute toxicity 2.5515 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.794
hERG inhibition (predictor II) Non-inhibitor 0.5837
Pharmacoeconomics
Manufacturers
  • Astrazeneca pharmaceuticals lp
Packagers
Dosage forms
FormRouteStrength
TabletOral16 mg
TabletOral32 mg
TabletOral4 mg
TabletOral8 mg
Prices
Unit descriptionCostUnit
Atacand 30 4 mg tablet Bottle75.98USDbottle
Atacand 30 8 mg tablet Bottle74.96USDbottle
Atacand hct 32-25 mg tablet3.64USDtablet
Atacand hct 32-12.5 mg tablet3.43USDtablet
Atacand 32 mg tablet3.36USDtablet
Atacand hct 16-12.5 mg tablet3.36USDtablet
Atacand 16 mg tablet2.49USDtablet
Atacand 4 mg tablet2.44USDtablet
Atacand 8 mg tablet2.44USDtablet
Atacand 16 mg Tablet1.28USDtablet
Atacand 32 mg Tablet1.28USDtablet
Atacand 8 mg Tablet1.28USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States55345341994-01-092014-01-09
United States57055171994-04-182011-04-18
Canada20833052003-12-092012-11-19
Canada20409551998-02-032011-04-22
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP6.1Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00771ALOGPS
logP4.02ALOGPS
logP5.05ChemAxon
logS-4.8ALOGPS
pKa (Strongest Acidic)2.97ChemAxon
pKa (Strongest Basic)1.71ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area118.81 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity134.92 m3·mol-1ChemAxon
Polarizability45.35 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Marina Etinger, Boris Fedotev, Ben-Zion Dolitzky, “Preparation of candesartan cilexetil.” U.S. Patent US20050131037, issued June 16, 2005.

US20050131037
General Reference
  1. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J, Yusuf S, Pocock S: Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003 Sep 6;362(9386):759-66. Pubmed
  2. Mendis B, Page SR: Candesartan: widening indications for this angiotensin II receptor blocker? Expert Opin Pharmacother. 2009 Aug;10(12):1995-2007. Pubmed
  3. Baguet JP, Barone-Rochette G, Neuder Y: Candesartan cilexetil in the treatment of chronic heart failure. Vasc Health Risk Manag. 2009;5(1):257-64. Epub 2009 Apr 8. Pubmed
  4. Bader, M. (2004). Renin-angiotensin-aldosterone system. In S. Offermanns, & W. Rosenthal (Eds.). Encyclopedic reference of molecular pharmacology (pp. 810-814). Berlin, Germany: Springer.
  5. Stanfield, C.L., & Germann, W.J. (2008). Principles of human physiology (3 rd ed.). San Francisco, CA: Pearson Education, Inc.
External Links
ResourceLink
KEGG DrugD00626
KEGG CompoundC07468
PubChem Compound2541
PubChem Substance46508342
ChemSpider2445
BindingDB50240609
ChEBI3347
ChEMBLCHEMBL1016
Therapeutic Targets DatabaseDAP001442
PharmGKBPA448765
IUPHAR587
Guide to Pharmacology587
Drug Product Database2239091
RxListhttp://www.rxlist.com/cgi/generic/candesar.htm
Drugs.comhttp://www.drugs.com/cdi/candesartan.html
WikipediaCandesartan
ATC CodesC09CA06
AHFS Codes
  • 24:32.08
PDB EntriesNot Available
FDA labelshow(49.4 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AmilorideIncreased risk of hyperkalemia
DrospirenoneIncreased risk of hyperkalemia
LithiumThe ARB increases serum levels of lithium
PotassiumIncreased risk of hyperkalemia
SpironolactoneIncreased risk of hyperkalemia
TobramycinIncreased risk of nephrotoxicity
TrandolaprilThe angiotensin II receptor blocker, Candesartan, may increase the adverse effects of Trandolapril.
TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
TriamtereneIncreased risk of hyperkalemia
Food Interactions
  • Administer on a regular basis, at about the same time each day.
  • Take without regard to meals.

Targets

1. Type-1 angiotensin II receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Type-1 angiotensin II receptor P30556 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Cervenka L, Navar LG: Renal responses of the nonclipped kidney of two-kidney/one-clip Goldblatt hypertensive rats to type 1 angiotensin II receptor blockade with candesartan. J Am Soc Nephrol. 1999 Jan;10 Suppl 11:S197-201. Pubmed
  3. Malmqvist K, Kahan T, Dahl M: Angiotensin II type 1 (AT1) receptor blockade in hypertensive women: benefits of candesartan cilexetil versus enalapril or hydrochlorothiazide. Am J Hypertens. 2000 May;13(5 Pt 1):504-11. Pubmed
  4. Wada T, Inada Y, Ojima M, Sanada T, Shibouta Y, Nishikawa K: Comparison of the antihypertensive effects of the new angiotensin II (AT1) receptor antagonist candesartan cilexetil (TCV-116) and the angiotensin converting enzyme inhibitor enalapril in rats. Hypertens Res. 1996 Jun;19(2):75-81. Pubmed
  5. Engelhorn T, Doerfler A, Heusch G, Schulz R: Reduction of cerebral infarct size by the AT1-receptor blocker candesartan, the HMG-CoA reductase inhibitor rosuvastatin and their combination. An experimental study in rats. Neurosci Lett. 2006 Oct 2;406(1-2):92-6. Epub 2006 Aug 9. Pubmed
  6. Caballero-George C, Vanderheyden PM, Solis PN, Gupta MP, Pieters L, Vauquelin G, Vlietinck A: In vitro effect of sanguinarine alkaloid on binding of [3H]candesartan to the human angiotensin AT1 receptor. Eur J Pharmacol. 2003 Jan 5;458(3):257-62. Pubmed
  7. McInnes GT, O’Kane KP, Istad H, Keinanen-Kiukaanniemi S, Van Mierlo HF: Comparison of the AT1-receptor blocker, candesartan cilexetil, and the ACE inhibitor, lisinopril, in fixed combination with low dose hydrochlorothiazide in hypertensive patients. J Hum Hypertens. 2000 Apr;14(4):263-9. Pubmed
  8. Vauquelin G, Fierens F, Van Liefde I: Long-lasting angiotensin type 1 receptor binding and protection by candesartan: comparison with other biphenyl-tetrazole sartans. J Hypertens Suppl. 2006 Mar;24(1):S23-30. Pubmed
  9. Mendis B, Page SR: Candesartan: widening indications for this angiotensin II receptor blocker? Expert Opin Pharmacother. 2009 Aug;10(12):1995-2007. Pubmed
  10. Meredith PA: Candesartan cilexetil—a review of effects on cardiovascular complications in hypertension and chronic heart failure. Curr Med Res Opin. 2007 Jul;23(7):1693-705. Pubmed
  11. Baguet JP, Barone-Rochette G, Neuder Y: Candesartan cilexetil in the treatment of chronic heart failure. Vasc Health Risk Manag. 2009;5(1):257-64. Epub 2009 Apr 8. Pubmed

Enzymes

1. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. McClellan KJ, Goa KL: Candesartan cilexetil. A review of its use in essential hypertension. Drugs. 1998 Nov;56(5):847-69. Pubmed
  2. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. Walsky RL, Gaman EA, Obach RS: Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol. 2005 Jan;45(1):68-78. Pubmed

3. UDP-glucuronosyltransferase 1-3

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-3 P35503 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

4. Prostaglandin G/H synthase 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Prostaglandin G/H synthase 1 P23219 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Takara K, Kakumoto M, Tanigawara Y, Funakoshi J, Sakaeda T, Okumura K: Interaction of digoxin with antihypertensive drugs via MDR1. Life Sci. 2002 Feb 15;70(13):1491-500. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12