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Identification
Name Candesartan
Accession Number DB00796 (APRD00420)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Candesartan cilexetil
Salts Not Available
Brand names
Name Company
Amias Eureco (Netherlands), Takeda (United Kingdom)
Atacand AstraZeneca
Blopress Takeda
Brand mixtures
Brand Name Ingredients
Atacand Plus Candesartan Cilexetil + Hydrochlorothiazide
Categories
  • Antihypertensive Agents
  • Angiotensin II Receptor Antagonists
  • Angiotensin II Type 1 Receptor Blockers
CAS number 139481-59-7
Weight Average: 440.454
Monoisotopic: 440.159688536
Chemical Formula C24H20N6O3
InChI Key InChIKey=HTQMVQVXFRQIKW-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)
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Biphenyltetrazoles and Derivatives
Substructures
  • Hydroxy Compounds
  • Benzyl Alcohols and Derivatives
  • Acetates
  • Benzoates
  • Benzimidazoles
  • Phenylpropenes
  • Ethers
  • Benzene and Derivatives
  • Biphenyl and Derivatives
  • Biphenyltetrazoles and Derivatives
  • Carboxylic Acids and Derivatives
  • Tetrazoles
  • Imidazoles
  • Phenyltetrazoles and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Imines
  • Benzoyl Derivatives
  • Cyanamides
Pharmacology
Indication May 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.
Pharmacodynamics Candesartan 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 action Candesartan 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.
Absorption Following 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 binding Candesartan 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.
Route of elimination When 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 life Approximately 9 hours.
Clearance
  • 0.37 mL/min/kg
Toxicity No 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 Not Available
Pharmacoeconomics
Manufacturers
  • Astrazeneca pharmaceuticals lp
Packagers
Dosage forms
Form Route Strength
Tablet Oral 16 mg
Tablet Oral 32 mg
Tablet Oral 4 mg
Tablet Oral 8 mg
Prices
Unit description Cost Unit
Atacand 30 4 mg tablet Bottle 75.98 USD bottle
Atacand 30 8 mg tablet Bottle 74.96 USD bottle
Atacand hct 32-25 mg tablet 3.64 USD tablet
Atacand hct 32-12.5 mg tablet 3.43 USD tablet
Atacand 32 mg tablet 3.36 USD tablet
Atacand hct 16-12.5 mg tablet 3.36 USD tablet
Atacand 16 mg tablet 2.49 USD tablet
Atacand 4 mg tablet 2.44 USD tablet
Atacand 8 mg tablet 2.44 USD tablet
Atacand 16 mg Tablet 1.28 USD tablet
Atacand 32 mg Tablet 1.28 USD tablet
Atacand 8 mg Tablet 1.28 USD tablet
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Patents
Country Patent Number Approved Expires (estimated)
United States 5534534 1994-01-09 2014-01-09
United States 5705517 1994-04-18 2011-04-18
Canada 2083305 2003-12-09 2012-11-19
Canada 2040955 1998-02-03 2011-04-22
Properties
State solid
Experimental Properties
Property Value Source
logP 6.1 Not Available
Predicted Properties
Property Value Source
water solubility 7.71e-03 g/l ALOGPS
logP 4.02 ALOGPS
logP 5.05 ChemAxon
logS -4.8 ALOGPS
pKa (strongest acidic) 2.97 ChemAxon
pKa (strongest basic) 1.71 ChemAxon
physiological charge -1 ChemAxon
hydrogen acceptor count 7 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 118.81 ChemAxon
rotatable bond count 7 ChemAxon
refractivity 134.92 ChemAxon
polarizability 45.35 ChemAxon
References
Synthesis Reference Not Available
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
Resource Link
KEGG Drug D00626 Link_out
KEGG Compound C07468 Link_out
PubChem Compound 2541 Link_out
PubChem Substance 46508342 Link_out
ChemSpider 2445 Link_out
BindingDB 50240609 Link_out
ChEBI 3347 Link_out
ChEMBL 3347 Link_out
Therapeutic Targets Database DAP001442 Link_out
PharmGKB PA448765 Link_out
IUPHAR 587 Link_out
Guide to Pharmacology 587 Link_out
Drug Product Database 2239091 Link_out
RxList http://www.rxlist.com/cgi/generic/candesar.htm Link_out
Drugs.com http://www.drugs.com/cdi/candesartan.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Candesartan Link_out
ATC Codes
  • C09CA06
AHFS Codes
  • 24:32.08
PDB Entries Not Available
FDA label show (49.4 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Amiloride Increased risk of hyperkalemia
Drospirenone Increased risk of hyperkalemia
Lithium The ARB increases serum levels of lithium
Potassium Increased risk of hyperkalemia
Spironolactone Increased risk of hyperkalemia
Tobramycin Increased risk of nephrotoxicity
Trandolapril The angiotensin II receptor blocker, Candesartan, may increase the adverse effects of Trandolapril.
Treprostinil Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Triamterene Increased 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

Pharmacological action: yes
Actions: antagonist

Receptor for angiotensin II. Mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system

Organism class: human
UniProt ID: P30556 Link_out
Gene: AGTR1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol)

UniProt ID: P10632 Link_out
Gene: CYP2C8
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds

UniProt ID: P35503 Link_out
Gene: UGT1A3 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

May play an important role in regulating or promoting cell proliferation in some normal and neoplastically transformed cells

UniProt ID: P23219 Link_out
Gene: PTGS1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19