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Identification
Name Tadalafil
Accession Number DB00820 (APRD00071)
Type small molecule
Groups approved
Description

Tadalafil is an orally adminstered drug used to treat male erectile dysfunction (impotence). It is marketed worldwide under the brand name Cialis. It is a phosphodiesterase 5 (PDE5) inhibitor. Tadalafil’s distinguishing pharmacologic feature is its longer half-life (17.5 hours) compared with Viagra and Levitra (4-5 hours). This longer half-life results in a longer duration of action and is, in part, responsible for the Cialis nickname of the “weekend pill.” This longer half-life also is the basis of current investigation for tadalafil’s use in pulmonary arterial hypertension as a once-daily therapy. [Wikipedia]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • CIA
  • ICOS 351
  • tadalafil
  • Tadanafil
Brand names
  • Cialis (Eli Lilly)
Brand name mixtures Not Available
Categories
  • Vasodilator Agents
  • Phosphodiesterase Inhibitors
CAS number 171596-29-5
Weight Average: 389.404
Monoisotopic: 389.137556111
Chemical Formula C22H19N3O4
InChI Key InChIKey=WOXKDUGGOYFFRN-IIBYNOLFSA-N
InChI
InChI=1S/C22H19N3O4/c1-24-10-19(26)25-16(22(24)27)9-14-13-4-2-3-5-15(13)23-20(14)21(25)12-6-7-17-18(8-12)29-11-28-17/h2-8,16,21,23H,9-11H2,1H3/t16-,21-/m1/s1
Plain Text
IUPAC Name
(2R,8R)-2-(2H-1,3-benzodioxol-5-yl)-6-methyl-3,6,17-triazatetracyclo[8.7.0.0^{3,8}.0^{11,16}]heptadeca-1(10),11(16),12,14-tetraene-4,7-dione
SMILES
[H][C@]12CC3=C(NC4=C3C=CC=C4)[C@H](N1C(=O)CN(C)C2=O)C1=CC2=C(OCO2)C=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Tryptamines and Derivatives
  • Lactams
Substructures
  • Acetals and Derivatives
  • Indoles and Indole Derivatives
  • Phenols and Derivatives
  • Amino Ketones
  • Pyrroles
  • Piperazines
  • Ethers
  • Benzene and Derivatives
  • Aliphatic and Aryl Amines
  • Tryptamines and Derivatives
  • Dioxoles
  • Catechols
  • Heterocyclic compounds
  • Aromatic compounds
  • Benzodioxoles
  • Anisoles
  • Carboxamides and Derivatives
  • Lactams
  • Imines
  • Phenyl Esters
Pharmacology
Indication Used for the treatment of erectile dysfunction.
Pharmacodynamics Tadalafil 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. Tadalafil 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 tadalafil 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, tadalafil should not cause an erection.
Mechanism of action Tadalafil 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 tadalafil enhances erectile function by increasing the amount of cGMP.
Absorption After single oral-dose administration, the maximum observed plasma concentration (Cmax) of tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours). Absolute bioavailability of tadalafil following oral dosing has not been determined.
Volume of distribution
  • 63 L
Protein binding 94%
Metabolism

Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. In vitro data suggests the metabolites are not expected to be pharmacologically active at observed metabolite concentrations.
Route of elimination Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Half life 17.5 hours
Clearance
  • oral cl=2.5 L/hr
Toxicity Oral, Rat LD50 = 2000 mg/kg, no deaths or toxicity.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Eli lilly co
  • Eli lilly and co
  • Eli Lilly and Company
Packagers
Dosage forms
Form Route Strength
Tablet, film coated Oral 10 mg
Tablet, film coated Oral 2.5 mg
Tablet, film coated Oral 20 mg
Tablet, film coated Oral 5 mg
Prices
Unit description Cost Unit
Cialis 30 5 mg tablet Box 140.77 USD box
Cialis 10 mg tablet 20.92 USD tablet
Cialis 20 mg tablet 20.92 USD tablet
Cialis 2.5 mg tablet 4.76 USD tablet
Cialis 5 mg tablet 4.76 USD tablet
Patents
Country Patent Number Approved Expires
United States 6821975 2000-11-19 2020-11-19
United States 6140329 1996-07-11 2016-07-11
Canada 2379948 2008-03-25 2020-04-26
Canada 2181377 2002-05-28 2015-01-19
Properties
State solid
Melting point 301-302 oC
Experimental Properties
Property Value Source
water solubility Practically insoluble in water PhysProp
logP 1.7 PhysProp
Predicted Properties
Property Value Source
water solubility 2.50e-01 g/l ALOGPS
logP 2.36 ALOGPS
logP 1.64 ChemAxon Molconvert
logS -3.19 ALOGPS
pKa 18.74 ChemAxon Molconvert
hydrogen acceptor count 4 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 74.87 ChemAxon Molconvert
rotatable bond count 1 ChemAxon Molconvert
refractivity 104.08 ChemAxon Molconvert
polarizability 40.92 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Naeije R, Huez S: Expert opinion on available options treating pulmonary arterial hypertension. Expert Opin Pharmacother. 2007 Oct;8(14):2247-65. Pubmed
  2. Burnett AL: Molecular Pharmacotherapeutic Targeting of PDE5 for Preservation of Penile Health. J Androl. 2007 Oct 17;. Pubmed
  3. Guazzi M, Samaja M: The role of PDE5-inhibitors in cardiopulmonary disorders: from basic evidence to clinical development. Curr Med Chem. 2007;14(20):2181-91. Pubmed
External Links
Resource Link
KEGG Drug D02008 Link_out
PubChem Compound 110635 Link_out
PubChem Substance 46507646 Link_out
ChemSpider 99301 Link_out
BindingDB 14777 Link_out
Therapeutic Targets Database DAP000615 Link_out
PharmGKB PA10333 Link_out
HET CIA Link_out
Drug Product Database 2248088 Link_out
RxList http://www.rxlist.com/cgi/generic3/cialis.htm Link_out
Drugs.com http://www.drugs.com/tadalafil.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/cia1687.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Tadalafil Link_out
ATC Codes
  • G04BE08
AHFS Codes
  • 24:12.12
PDB Entries Not Available
FDA label show (286.8 KB)
MSDS show (73.7 KB)
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. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Curran M, Keating G: Tadalafil. Drugs. 2003;63(20):2203-12; discussion 2213-4. Pubmed
  3. Eardley I, Cartledge J: Tadalafil (Cialis) for men with erectile dysfunction. Int J Clin Pract. 2002 May;56(4):300-4. Pubmed
  4. Montorsi F, Salonia A, Deho’ F, Cestari A, Guazzoni G, Rigatti P, Stief C: Pharmacological management of erectile dysfunction. BJU Int. 2003 Mar;91(5):446-54. Pubmed
  5. Rotella DP: Tadalafil Lilly ICOS. Curr Opin Investig Drugs. 2003 Jan;4(1):60-5. Pubmed
  6. Roumeguere T, Sternon J, Schulman CC: [Erectile dysfunction and phosphodiesterase type 5 inhibitors] Rev Med Brux. 2003 Jun;24(3):169-75. Pubmed
  7. 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. Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A

Pharmacological action: unknown
Actions: inhibitor

Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides cAMP and cGMP. Catalyzes the hydrolysis of both cAMP and cGMP to 5'-AMP and 5'- GMP, respectively

Organism class: human
UniProt ID: Q9HCR9 Link_out
Gene: PDE11A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Cialis. Product Monograph. Eli Lilly Canada. March 2009
  2. Weeks JL 2nd, Corbin JD, Francis SH: Interactions between cyclic nucleotide phosphodiesterase 11 catalytic site and substrates or tadalafil and role of a critical Gln-869 hydrogen bond. J Pharmacol Exp Ther. 2009 Oct;331(1):133-41. Epub 2009 Jul 29. Pubmed
  3. Weeks JL 2nd, Zoraghi R, Francis SH, Corbin JD: N-Terminal domain of phosphodiesterase-11A4 (PDE11A4) decreases affinity of the catalytic site for substrates and tadalafil, and is involved in oligomerization. Biochemistry. 2007 Sep 11;46(36):10353-64. Epub 2007 Aug 16. Pubmed
Enzymes

1. Cytochrome P450 3A4

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

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