Banner
Identification
Name Valsartan
Accession Number DB00177 (APRD00133)
Type small molecule
Groups approved
Description

Valsartan is an angiotensin-receptor blocker (ARB) that may be used to treat a variety of cardiac conditions including hypertension, diabetic nephropathy and heart failure. Valsartan 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. Valsartan 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
  • valsartan
Brand names
  • Diovan (Novartis)
  • Valsarran
Brand name mixtures Not Available
Categories
  • Antihypertensive Agents
  • Angiotensin II Receptor Antagonists
CAS number 137862-53-4
Weight Average: 435.5188
Monoisotopic: 435.227039819
Chemical Formula C24H29N5O3
InChI Key InChIKey=ACWBQPMHZXGDFX-QFIPXVFZSA-N
InChI
InChI=1S/C24H29N5O3/c1-4-5-10-21(30)29(22(16(2)3)24(31)32)15-17-11-13-18(14-12-17)19-8-6-7-9-20(19)23-25-27-28-26-23/h6-9,11-14,16,22H,4-5,10,15H2,1-3H3,(H,31,32)(H,25,26,27,28)/t22-/m0/s1
Plain Text
IUPAC Name
(2S)-3-methyl-2-[N-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)pentanamido]butanoic acid
SMILES
CCCCC(=O)N(CC1=CC=C(C=C1)C1=C(C=CC=C1)C1=NNN=N1)[C@@H](C(C)C)C(O)=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Biphenyltetrazoles and Derivatives
Substructures
  • Hydroxy Compounds
  • Acetates
  • Amino Ketones
  • Phenylpropenes
  • Benzene and Derivatives
  • Aliphatic and Aryl Amines
  • Biphenyl and Derivatives
  • Biphenyltetrazoles and Derivatives
  • Carboxylic Acids and Derivatives
  • Tetrazoles
  • Phenyltetrazoles and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Imines
  • 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. Losartan 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 Valsartan belongs to a class of antihypertensive agents called angiotensin II receptor blockers (ARBs). Valsartan is a specific and selective type-1 angiotensin II receptor (AT1) antagonist which blocks the blood pressure increasing effects angiotensin II via the renin-angiotensin-aldosterone system (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: 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 Valsartan is an ARB that selectively inhibits the binding of angiotensin II to AT1, which is found in many tissues such as vascular smooth muscle and the adrenal glands. This effectively inhibits the AT1-mediated vasoconstrictive and aldosterone-secreting effects of angiotensin II and results in a decrease in vascular resistance and blood pressure. Valsartan is selective for AT1 and has virtually no affinity for AT2. Inhibition of aldosterone secretion may inhibit sodium and water reabsorption in the kidneys while decreasing potassium excretion. The primary metabolite of valsartan, valeryl 4-hydroxy valsartan, has no pharmacological activity.
Absorption Absolute bioavailability = 23% with high variability
Volume of distribution
  • 17 L (low tissue distribution)
Protein binding 94 - 97% bound to serum proteins, primarily serum albumin
Metabolism

Valsartan is excreted largely as unchanged drug (80%) and is minimally metabolized in humans. The primary circulating metabolite, 4-OH-valsartan, is pharmacologically inactive and produced CYP2C9. 4-OH-valsartan accounts for approximately 9% of the circulating dose of valsartan. Although valsartan is metabolized by CYP2C9, CYP-mediated drug-drug interactions between valsartan and other drugs is unlikely.

Enzyme Metabolite Reaction Km Vmax
Cytochrome P450 2C9 4-Hydroxyvalsartan 4-hydroxylation
Route of elimination 83% of absorbed valsartan is excreted in feces and 13% is excreted in urine, primarily as unchanged drug
Half life The initial phase t1/2 α is < 1 hour while the terminal phase t1/2 β is 5-9 hours.
Clearance
  • 2 L/h [IV administration]
  • 4.5 L/h [heart Failure patients receiving oral administration 40 to 160 mg twice a day]
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
  • Novartis Corporation
Packagers
Dosage forms
Form Route Strength
Tablet Oral 160 mg
Tablet Oral 320 mg
Tablet Oral 40 mg
Tablet Oral 80 mg
Prices
Unit description Cost Unit
Diovan hct 320-25 mg tablet 4.63 USD tablet
Diovan hct 320-12.5 mg tablet 4.1 USD tablet
Diovan hct 160-25 mg tablet 3.66 USD tablet
Diovan hct 160-12.5 mg tablet 3.27 USD tablet
Diovan 320 mg tablet 3.17 USD tablet
Diovan hct 80-12.5 mg tablet 3.0 USD tablet
Diovan 160 mg tablet 2.42 USD tablet
Diovan 80 mg tablet 2.33 USD tablet
Diovan 40 mg tablet 2.32 USD tablet
Patents
Country Patent Number Approved Expires
United States 6294197 1997-12-18 2017-12-18
United States 5399578 1995-03-21 2012-03-21
Canada 2259148 2009-09-29 2017-06-18
Canada 2036427 1998-12-29 2011-02-15
Properties
State solid
Melting point 116-117oC
Experimental Properties
Property Value Source
logP 5.8 PhysProp
Predicted Properties
Property Value Source
water solubility 2.34e-02 g/l ALOGPS
logP 3.68 ALOGPS
logP 5.27 ChemAxon Molconvert
logS -4.27 ALOGPS
pKa 8.15 ChemAxon Molconvert
hydrogen acceptor count 6 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 112.07 ChemAxon Molconvert
rotatable bond count 10 ChemAxon Molconvert
refractivity 134.77 ChemAxon Molconvert
polarizability 47.27 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Bader, M. (2004). Renin-angiotensin-aldosterone system. In S. Offermanns, & W. Rosenthal (Eds.). Encyclopedic reference of molecular pharmacology (pp. 810-814). Berlin, Germany: Springer.
  2. Diovan. (2009). [Electronic version]. e-CPS. Retrieved December 28, 2009.
  3. 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 D00400 Link_out
PubChem Compound 60846 Link_out
PubChem Substance 46509000 Link_out
ChemSpider 54833 Link_out
BindingDB 50049186 Link_out
ChEBI 9927 Link_out
ChEMBL 9927 Link_out
Therapeutic Targets Database DAP000363 Link_out
PharmGKB PA451848 Link_out
Drug Product Database 2244781 Link_out
RxList http://www.rxlist.com/cgi/generic/valsartan.htm Link_out
Drugs.com http://www.drugs.com/cdi/valsartan.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Valsartan Link_out
ATC Codes
  • C09CA03
AHFS Codes
  • 24:32.08
PDB Entries Not Available
FDA label show (237 KB)
MSDS show (36.2 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
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. Azizi M, Menard J, Bissery A, Guyenne TT, Bura-Riviere A, Vaidyanathan S, Camisasca RP: Pharmacologic demonstration of the synergistic effects of a combination of the renin inhibitor aliskiren and the AT1 receptor antagonist valsartan on the angiotensin II-renin feedback interruption. J Am Soc Nephrol. 2004 Dec;15(12):3126-33. Pubmed
  3. Criscione L, de Gasparo M, Buhlmayer P, Whitebread S, Ramjoue HP, Wood J: Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT1-receptor subtype. Br J Pharmacol. 1993 Oct;110(2):761-71. Pubmed
  4. Shargorodsky M, Leibovitz E, Lubimov L, Gavish D, Zimlichman R: Prolonged treatment with the AT1 receptor blocker, valsartan, increases small and large artery compliance in uncomplicated essential hypertension. Am J Hypertens. 2002 Dec;15(12):1087-91. Pubmed
  5. de Gasparo M, Whitebread S: Binding of valsartan to mammalian angiotensin AT1 receptors. Regul Pept. 1995 Nov 10;59(3):303-11. Pubmed
  6. Siragy HM, El-Kersh MA, De Gasparo M, Webb RL, Carey RM: Differences in AT2 -receptor stimulation between AT1 -receptor blockers valsartan and losartan quantified by renal interstitial fluid cGMP. J Hypertens. 2002 Jun;20(6):1157-63. 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. 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
  2. Nakashima A, Kawashita H, Masuda N, Saxer C, Niina M, Nagae Y, Iwasaki K: Identification of cytochrome P450 forms involved in the 4-hydroxylation of valsartan, a potent and specific angiotensin II receptor antagonist, in human liver microsomes. Xenobiotica. 2005 Jun;35(6):589-602. 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
Transporters

1. Solute carrier organic anion transporter family member 1B3

Actions: substrate

Mediates the Na(+)-independent transport of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotrexate and sulfobromophthalein (BSP)

UniProt ID: Q9NPD5 Link_out
Gene: SLCO1B3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Poirier A, Cascais AC, Funk C, Lave T: Prediction of pharmacokinetic profile of valsartan in human based on in vitro uptake transport data. J Pharmacokinet Pharmacodyn. 2009 Dec;36(6):585-611. Epub 2009 Nov 20. Pubmed
  2. Poirier A, Cascais AC, Funk C, Lave T: Prediction of pharmacokinetic profile of valsartan in humans based on in vitro uptake-transport data. Chem Biodivers. 2009 Nov;6(11):1975-87. Pubmed

2. Solute carrier organic anion transporter family member 1B1

Actions: substrate

Mediates the Na(+)-independent transport of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostaglandin E2, thromboxane B2, leukotriene C3, leukotriene E4, thyroxine and triiodothyronine. May play an important role in the clearance of bile acids and organic anions from the liver

UniProt ID: Q9Y6L6 Link_out
Gene: SLCO1B1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Poirier A, Cascais AC, Funk C, Lave T: Prediction of pharmacokinetic profile of valsartan in human based on in vitro uptake transport data. J Pharmacokinet Pharmacodyn. 2009 Dec;36(6):585-611. Epub 2009 Nov 20. Pubmed
  2. Poirier A, Cascais AC, Funk C, Lave T: Prediction of pharmacokinetic profile of valsartan in humans based on in vitro uptake-transport data. Chem Biodivers. 2009 Nov;6(11):1975-87. Pubmed
Carriers

1. Serum albumin

Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood

UniProt ID: P02768 Link_out
Gene: ALB Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Diovan. (2009). [Electronic version]. e-CPS. Retrieved September 15, 2011.
Comments
Drug created on June 13, 2005 07:24 / Updated on September 15, 2011 14:53

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.