Banner
targets (3) enzymes (2)
for drugs
Identification
Name Vardenafil
Accession Number DB00862 (APRD00699)
Type small molecule
Groups approved
Description

Vardenafil (Levitra) is an oral therapy for the treatment of erectile dysfunction. It is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Penile erection is a hemodynamic process initiated by the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles. During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpus cavernosum. Nitric oxide activates the enzyme guanylate cyclase resulting in increased synthesis of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum. The cGMP in turn triggers smooth muscle relaxation, allowing increased blood flow into the penis, resulting in erection. The tissue concentration of cGMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs). The most abundant PDE in the human corpus cavernosum is the cGMPspecific phosphodiesterase type 5 (PDE5); therefore, the inhibition of PDE5 enhances erectile function by increasing the amount of cGMP.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • VDN
Brand names
  • Levitra
Brand name mixtures Not Available
Categories
  • Vasoconstrictor Agents
  • Phosphodiesterase Inhibitors
  • Anti-Impotence Agents
CAS number 224785-90-4
Weight Average: 488.603
Monoisotopic: 488.220574232
Chemical Formula C23H32N6O4S
InChI Key InChIKey=SECKRCOLJRRGGV-UHFFFAOYSA-N
InChI
InChI=1S/C23H32N6O4S/c1-5-8-20-24-16(4)21-23(30)25-22(26-29(20)21)18-15-17(9-10-19(18)33-7-3)34(31,32)28-13-11-27(6-2)12-14-28/h9-10,15H,5-8,11-14H2,1-4H3,(H,25,26,30)
Plain Text
IUPAC Name
2-[2-ethoxy-5-(4-ethylpiperazine-1-sulfonyl)phenyl]-5-methyl-7-propyl-1H,4H-imidazo[4,3-f][1,2,4]triazin-4-one
SMILES
CCCC1=NC(C)=C2N1NC(=NC2=O)C1=C(OCC)C=CC(=C1)S(=O)(=O)N1CCN(CC)CC1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Benzenesulfonamides
Substructures
  • Phenols and Derivatives
  • Sulfonyls
  • Piperazines
  • Ethers
  • Benzene and Derivatives
  • Benzenesulfonamides
  • Aliphatic and Aryl Amines
  • Imidazoles
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Sulfonamides
  • Triazines
  • Imines
  • Cyanamides
  • Phenyl Esters
Pharmacology
Indication Used for the treatment of erectile dysfunction
Pharmacodynamics Vardenafil is used to treat male erectile dysfunction (impotence) and pulmonary arterial hypertension (PAH). Part of the physiological process of erection involves the release of nitric oxide (NO) in the corpus cavernosum. This then activates the enzyme guanylate cyclase which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation in the corpus cavernosum, resulting in increased inflow of blood and an erection. Vardenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum. This means that, with vardenafil on board, normal sexual stimulation leads to increased levels of cGMP in the corpus cavernosum which leads to better erections. Without sexual stimulation and no activation of the NO/cGMP system, vardenafil should not cause an erection.
Mechanism of action Vardenafil inhibits the cGMP specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum located around the penis. Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) by vardenafil enhances erectile function by increasing the amount of cGMP.
Absorption Vardenafil is rapidly absorbed with absolute bioavailability of approximately 15%.
Volume of distribution
  • 208 L
Protein binding 95%
Metabolism

Vardenafil is metabolized predominantly by the hepatic enzyme CYP3A4, with contribution from the CYP3A5 and CYP2C isoforms. The major circulating metabolite, M1, results from desethylation at the piperazine moiety of vardenafil. M1 shows a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 28% of that of vardenafil.
Route of elimination After oral administration, vardenafil is excreted as metabolites predominantly in the feces (approximately 91-95% of administered oral dose) and to a lesser extent in the urine (approximately 2-6% of administered oral dose).
Half life 4-5 hours
Clearance
  • 56 L/h
Toxicity Symptoms of overdose include vision changes and back and muscle pain.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Bayer healthcare pharmaceuticals inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Levitra 10 mg tablet 19.04 USD tablet
Levitra 20 mg tablet 19.04 USD tablet
Levitra 5 mg tablet 19.04 USD tablet
Levitra 2.5 mg tablet 18.66 USD tablet
Patents
Country Patent Number Approved Expires
United States 6362178 1998-10-31 2018-10-31
Canada 2309332 2002-12-03 2018-10-31
Properties
State solid
Melting point 192 oC
Experimental Properties
Property Value Source
water solubility 0.11 mg/mL (HCl salt) PhysProp
logP 1.4 PhysProp
Predicted Properties
Property Value Source
water solubility 3.25e-01 g/l ALOGPS
logP 2.18 ALOGPS
logP 1.32 ChemAxon Molconvert
logS -3.18 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 8 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 109.13 ChemAxon Molconvert
rotatable bond count 7 ChemAxon Molconvert
refractivity 142.71 ChemAxon Molconvert
polarizability 53.22 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
PubChem Compound 110634 Link_out
PubChem Substance 46506777 Link_out
ChemSpider 99300 Link_out
BindingDB 14776 Link_out
Therapeutic Targets Database DAP000414 Link_out
PharmGKB PA10229 Link_out
Drug Product Database 2250462 Link_out
RxList http://www.rxlist.com/cgi/generic3/levitra.htm Link_out
Drugs.com http://www.drugs.com/cdi/vardenafil.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/lev1688.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Vardenafil Link_out
ATC Codes
  • G04BE09
AHFS Codes
  • 24:12.12
PDB Entries Not Available
FDA label show (534.9 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. cGMP-specific 3',5'-cyclic phosphodiesterase

Pharmacological action: yes
Actions: inhibitor

Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'- GMP

Organism class: human
UniProt ID: O76074 Link_out
Gene: PDE5A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Blount MA, Zoraghi R, Ke H, Bessay EP, Corbin JD, Francis SH: A 46-amino acid segment in phosphodiesterase-5 GAF-B domain provides for high vardenafil potency over sildenafil and tadalafil and is involved in phosphodiesterase-5 dimerization. Mol Pharmacol. 2006 Nov;70(5):1822-31. Epub 2006 Aug 22. Pubmed
  2. Carrier S: Pharmacology of phosphodiesterase 5 inhibitors. Can J Urol. 2003 Feb;10 Suppl 1:12-6. Pubmed
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  4. Kim NN, Huang YH, Goldstein I, Bischoff E, Traish AM: Inhibition of cyclic GMP hydrolysis in human corpus cavernosum smooth muscle cells by vardenafil, a novel, selective phosphodiesterase type 5 inhibitor. Life Sci. 2001 Sep 28;69(19):2249-56. Pubmed
  5. Saenz de Tejada I, Angulo J, Cuevas P, Fernandez A, Moncada I, Allona A, Lledo E, Korschen HG, Niewohner U, Haning H, Pages E, Bischoff E: The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil. Int J Impot Res. 2001 Oct;13(5):282-90. Pubmed
  6. Scheen AJ: [Medication of the month. Vardenafil (Levitra)] Rev Med Liege. 2003 Sep;58(9):576-9. Pubmed
  7. Sung BJ, Hwang KY, Jeon YH, Lee JI, Heo YS, Kim JH, Moon J, Yoon JM, Hyun YL, Kim E, Eum SJ, Park SY, Lee JO, Lee TG, Ro S, Cho JM: Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules. Nature. 2003 Sep 4;425(6953):98-102. Pubmed
  8. Wang H, Ye M, Robinson H, Francis SH, Ke H: Conformational variations of both phosphodiesterase-5 and inhibitors provide the structural basis for the physiological effects of vardenafil and sildenafil. Mol Pharmacol. 2008 Jan;73(1):104-10. Epub 2007 Oct 24. Pubmed
  9. Zoraghi R, Francis SH, Corbin JD: Critical amino acids in phosphodiesterase-5 catalytic site that provide for high-affinity interaction with cyclic guanosine monophosphate and inhibitors. Biochemistry. 2007 Nov 27;46(47):13554-63. Epub 2007 Nov 3. Pubmed

2. Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit gamma

Pharmacological action: unknown
Actions: allosteric modulator

Participates in processes of transmission and amplification of the visual signal. cGMP-PDEs are the effector molecules in G-protein-mediated phototransduction in vertebrate rods and cones

Organism class: human
UniProt ID: P18545 Link_out
Gene: PDE6G Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhang XJ, Cahill KB, Elfenbein A, Arshavsky VY, Cote RH: Direct allosteric regulation between the GAF domain and catalytic domain of photoreceptor phosphodiesterase PDE6. J Biol Chem. 2008 Oct 31;283(44):29699-705. Epub 2008 Sep 8. Pubmed

3. Retinal cone rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit gamma

Pharmacological action: unknown
Actions: allosteric modulator

Participates in processes of transmission and amplification of the visual signal. cGMP-PDEs are the effector molecules in G-protein-mediated phototransduction in vertebrate rods and cones

Organism class: human
UniProt ID: Q13956 Link_out
Gene: PDE6H Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhang XJ, Cahill KB, Elfenbein A, Arshavsky VY, Cote RH: Direct allosteric regulation between the GAF domain and catalytic domain of photoreceptor phosphodiesterase PDE6. J Biol Chem. 2008 Oct 31;283(44):29699-705. Epub 2008 Sep 8. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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 3A5

Actions: substrate

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

UniProt ID: P20815 Link_out
Gene: CYP3A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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
Comments
Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:43

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.