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targets (5) enzymes (2)
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Identification
Name Darifenacin
Accession Number DB00496 (APRD00903)
Type small molecule
Groups approved
Description

Darifenacin (Enablex®, Novartis) is a medication used to treat urinary incontinence.

Darifenacin works by blocking the M3 muscarinic acetylcholine receptor, which is primarily responsible for bladder muscle contractions. It thereby decreases the urgency to urinate. It should not be used in people with urinary retention.

It is not known whether this selectivity for the M3 receptor translates into any clinical advantage when treating symptoms of overactive bladder syndrome.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • darifenacin
Brand names
  • Emselex
  • Enablex
Brand name mixtures Not Available
Categories
  • Muscarinic Antagonists
  • Urinary antispasmodics
CAS number 133099-04-4
Weight Average: 426.55
Monoisotopic: 426.230728214
Chemical Formula C28H30N2O2
InChI Key InChIKey=HXGBXQDTNZMWGS-RUZDIDTESA-N
InChI
InChI=1S/C28H30N2O2/c29-27(31)28(23-7-3-1-4-8-23,24-9-5-2-6-10-24)25-14-17-30(20-25)16-13-21-11-12-26-22(19-21)15-18-32-26/h1-12,19,25H,13-18,20H2,(H2,29,31)/t25-/m1/s1
Plain Text
IUPAC Name
2-[(3S)-1-[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]pyrrolidin-3-yl]-2,2-diphenylacetamide
SMILES
NC(=O)C([C@@H]1CCN(CCC2=CC3=C(OCC3)C=C2)C1)(C1=CC=CC=C1)C1=CC=CC=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Diphenylmethanes
Substructures
  • Carbonyl Compounds
  • Benzofurans
  • Phenols and Derivatives
  • Amino Ketones
  • Pyrrolidines
  • Ethers
  • Benzene and Derivatives
  • Carbamates and Derivatives
  • Aliphatic and Aryl Amines
  • Diphenylmethanes
  • Phenethylamines
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Carboxamides and Derivatives
  • Phenylpropylamines
  • Carboxylic Acids and Derivatives
  • Phenyl Esters
Pharmacology
Indication For the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency.
Pharmacodynamics Darifenacin is a competitive muscarinic receptor antagonist. In vitro studies using human recombinant muscarinic receptor subtypes show that darifenacin has greater affinity for the M3 receptor than for the other known muscarinic receptors (9 and 12-fold greater affinity for M3 compared to M1 and M5, respectively, and 59-fold greater affinity for M3 compared to both M2 and M4). Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of the urinary bladder smooth muscle and stimulation of salivary secretion. Adverse drug effects such as dry mouth, constipation and abnormal vision may be mediated through effects on M3 receptors in these organs.
Mechanism of action Darifenacin selectively antagonizes the muscarinic M3 receptor. M3 receptors are involved in contraction of human bladder and gastrointestinal smooth muscle, saliva production, and iris sphincter function.
Absorption The mean oral bioavailability at steady state is estimated to be 15% and 19% for 7.5 mg and 15 mg tablets, respectively.
Volume of distribution
  • 163 L
Protein binding Darifenacin is approximately 98% bound to plasma proteins (primarily to alpha-1-acid-glycoprotein).
Metabolism

Hepatic. Primarily mediated by the cytochrome P450 enzymes CYP2D6 and CYP3A4.
Route of elimination Not Available
Half life The elimination half-life of darifenacin following chronic dosing is approximately 13-19 hours.
Clearance
  • 40 L/h [extensive metabolizers]
  • 32 L/h [poor metabolizers]
Toxicity Overdosage can potentially result in severe central anticholinergic effects.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
Form Route Strength
Tablet, extended release Oral
Prices
Unit description Cost Unit
Enablex 15 mg 24 Hour tablet 5.22 USD tablet
Enablex 7.5 mg 24 Hour tablet 5.22 USD tablet
Enablex 15 mg tablet 5.02 USD tablet
Enablex 7.5 mg tablet 5.02 USD tablet
Patents
Country Patent Number Approved Expires
United States 6106864 1996-08-21 2016-08-21
United States 5096890 1995-03-13 2015-03-13
Canada 2469702 2010-07-06 2022-03-05
Canada 2230314 2003-06-24 2016-08-21
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
logP 4.5 PhysProp
Predicted Properties
Property Value Source
water solubility 2.98e-04 g/l ALOGPS
logP 4.35 ALOGPS
logP 4.54 ChemAxon Molconvert
logS -6.16 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 3 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 55.56 ChemAxon Molconvert
rotatable bond count 7 ChemAxon Molconvert
refractivity 128.37 ChemAxon Molconvert
polarizability 48.54 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D01699 Link_out
PubChem Compound 444031 Link_out
PubChem Substance 46508104 Link_out
ChemSpider 392054 Link_out
BindingDB 50109647 Link_out
ChEBI 391960 Link_out
ChEMBL 391960 Link_out
Therapeutic Targets Database DAP001131 Link_out
Drug Product Database 0 Link_out
RxList http://www.rxlist.com/cgi/generic3/enablex.htm Link_out
Drugs.com http://www.drugs.com/cdi/darifenacin-extended-release-tablets.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Darifenacin Link_out
ATC Codes
  • G04BD10
AHFS Codes
  • 86:12.00
PDB Entries Not Available
FDA label show (393.7 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions
  • Take without regard to meals.
Targets

1. Muscarinic acetylcholine receptor M3

Pharmacological action: yes
Actions: antagonist

The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover

Organism class: human
UniProt ID: P20309 Link_out
Gene: CHRM3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Bharucha AE, Ravi K, Zinsmeister AR: Comparison of selective M3 and nonselective muscarinic receptor antagonists on gastrointestinal transit and bowel habits in humans. Am J Physiol Gastrointest Liver Physiol. 2010 Jul;299(1):G215-9. Epub 2010 Apr 15. Pubmed
  2. Bozkurt TE, Sahin-Erdemli I: M(1) and M(3) muscarinic receptors are involved in the release of urinary bladder-derived relaxant factor. Pharmacol Res. 2009 May;59(5):300-5. Epub 2009 Feb 5. Pubmed
  3. Jha S, Parsons M: Treatment of overactive bladder in the aging population: focus on darifenacin. Clin Interv Aging. 2006;1(4):309-16. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Muscarinic acetylcholine receptor M1

Pharmacological action: unknown
Actions: antagonist

The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover

Organism class: human
UniProt ID: P11229 Link_out
Gene: CHRM1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Jha S, Parsons M: Treatment of overactive bladder in the aging population: focus on darifenacin. Clin Interv Aging. 2006;1(4):309-16. Pubmed
  2. Moriya H, Takagi Y, Nakanishi T, Hayashi M, Tani T, Hirotsu I: Affinity profiles of various muscarinic antagonists for cloned human muscarinic acetylcholine receptor (mAChR) subtypes and mAChRs in rat heart and submandibular gland. Life Sci. 1999;64(25):2351-8. Pubmed

3. Muscarinic acetylcholine receptor M2

Pharmacological action: unknown
Actions: antagonist

The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is adenylate cyclase inhibition

Organism class: human
UniProt ID: P08172 Link_out
Gene: CHRM2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Jha S, Parsons M: Treatment of overactive bladder in the aging population: focus on darifenacin. Clin Interv Aging. 2006;1(4):309-16. Pubmed
  2. Moriya H, Takagi Y, Nakanishi T, Hayashi M, Tani T, Hirotsu I: Affinity profiles of various muscarinic antagonists for cloned human muscarinic acetylcholine receptor (mAChR) subtypes and mAChRs in rat heart and submandibular gland. Life Sci. 1999;64(25):2351-8. Pubmed

4. Muscarinic acetylcholine receptor M4

Pharmacological action: unknown
Actions: antagonist

The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is inhibition of adenylate cyclase

Organism class: human
UniProt ID: P08173 Link_out
Gene: CHRM4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Jha S, Parsons M: Treatment of overactive bladder in the aging population: focus on darifenacin. Clin Interv Aging. 2006;1(4):309-16. Pubmed
  2. Moriya H, Takagi Y, Nakanishi T, Hayashi M, Tani T, Hirotsu I: Affinity profiles of various muscarinic antagonists for cloned human muscarinic acetylcholine receptor (mAChR) subtypes and mAChRs in rat heart and submandibular gland. Life Sci. 1999;64(25):2351-8. Pubmed

5. Muscarinic acetylcholine receptor M5

Pharmacological action: unknown
Actions: antagonist

The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover

Organism class: human
UniProt ID: P08912 Link_out
Gene: CHRM5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Moriya H, Takagi Y, Nakanishi T, Hayashi M, Tani T, Hirotsu I: Affinity profiles of various muscarinic antagonists for cloned human muscarinic acetylcholine receptor (mAChR) subtypes and mAChRs in rat heart and submandibular gland. Life Sci. 1999;64(25):2351-8. Pubmed
  2. Jha S, Parsons M: Treatment of overactive bladder in the aging population: focus on darifenacin. Clin Interv Aging. 2006;1(4):309-16. 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. Skerjanec A: The clinical pharmacokinetics of darifenacin. Clin Pharmacokinet. 2006;45(4):325-50. Pubmed

2. Cytochrome P450 2D6

Actions: substrate, inhibitor

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Skerjanec A: The clinical pharmacokinetics of darifenacin. Clin Pharmacokinet. 2006;45(4):325-50. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:04

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.