T3DB: Darifenacin

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (5)XML

Targets (5)

Record Information

Version

2.0

Creation Date

2009-07-30 17:58:49 UTC

Update Date

2014-12-24 20:26:07 UTC

Accession Number

T3D3499

Identification

Common Name

Darifenacin

Class

Small Molecule

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.

Compound Type

Amide
Amine
Antispasmodic Agent
Drug
Ether
Metabolite
Muscarinic Antagonist
Organic Compound
Synthetic Compound
Urinary Antispasmodic

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

Synonym
(S)-1-(2-(2,3-dihydro-5-Benzofuranyl)ethyl)-alpha,alpha-diphenyl-3-pyrrolidineacetamide
Darifenacina
Darifénacine
Darifenacinum
Emselex
Enablex
Xelena

Chemical Formula

C₂₈H₃₀N₂O₂

Average Molecular Mass

426.550 g/mol

Monoisotopic Mass

426.231 g/mol

CAS Registry Number

133099-04-4

IUPAC Name

2-[(3S)-1-[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]pyrrolidin-3-yl]-2,2-diphenylacetamide

Traditional Name

darifenacin

SMILES

[H][C@]1(CCN(CCC2=CC3=C(OCC3)C=C2)C1)C(C(O)=N)(C1=CC=CC=C1)C1=CC=CC=C1

InChI Identifier

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

InChI Key

InChIKey=HXGBXQDTNZMWGS-RUZDIDTESA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as diphenylmethanes. Diphenylmethanes are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.

Kingdom

Organic compounds

Super Class

Benzenoids

Class

Benzene and substituted derivatives

Sub Class

Diphenylmethanes

Direct Parent

Diphenylmethanes

Alternative Parents

Substituents

Diphenylmethane
Phenylacetamide
Phenethylamine
Coumaran
Alkyl aryl ether
Aralkylamine
N-alkylpyrrolidine
Pyrrolidine
Amino acid or derivatives
Carboxamide group
Primary carboxylic acid amide
Tertiary amine
Tertiary aliphatic amine
Ether
Carboxylic acid derivative
Oxacycle
Organoheterocyclic compound
Azacycle
Organic oxide
Organic nitrogen compound
Organopnictogen compound
Organooxygen compound
Organonitrogen compound
Organic oxygen compound
Amine
Carbonyl group
Hydrocarbon derivative
Aromatic heteropolycyclic compound

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

monocarboxylic acid amide (CHEBI:391960 )
1-benzofurans (CHEBI:391960 )
pyrrolidines (CHEBI:391960 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Not Available

Applications

Biological Roles

muscarinic antagonist

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	Not Available
Boiling Point	Not Available
Solubility	2.98e-04 g/L
LogP	4.5

Predicted Properties

Property	Value	Source
Water Solubility	0.0003 g/L	ALOGPS
logP	4.35	ALOGPS
logP	4.54	ChemAxon
logS	-6.2	ALOGPS
pKa (Strongest Acidic)	16.21	ChemAxon
pKa (Strongest Basic)	10.11	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	3	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	55.56 Å²	ChemAxon
Rotatable Bond Count	7	ChemAxon
Refractivity	128.37 m³·mol⁻¹	ChemAxon
Polarizability	48.54 Å³	ChemAxon
Number of Rings	5	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-00lv-2491000000-40c43db64189724fe0c2	2017-09-01	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-004i-0101900000-1979d23256753a983573	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-03gj-0756900000-6e69c78743e94527add2	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0uxs-2910000000-ec1acf0e02b7c0a392f3	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-004i-0001900000-e8c519b1d7f130de607a	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-004i-4285900000-73144c3d58ba99d76581	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0006-9030000000-5dfb7a1ae0753d3d4c11	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-005c-4005900000-8a58ca84e09117fd29e5	2021-09-22	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0006-9004100000-2c811675031a777fbc67	2021-09-22	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0006-9212000000-514c545cfeaf92ef3a8e	2021-09-22	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-004i-0002900000-3905ca525d1dcc4e15f3	2021-09-22	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-004i-0104900000-359dc4da59d626f0edf4	2021-09-22	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0002-0932000000-13b487199d725fb1e357	2021-09-22	View Spectrum

Toxicity Profile

Route of Exposure

The mean oral bioavailability at steady state is estimated to be 15% and 19% for 7.5 mg and 15 mg tablets, respectively.

Mechanism of Toxicity

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.

Metabolism

Hepatic. Primarily mediated by the cytochrome P450 enzymes CYP2D6 and CYP3A4. Half Life: The elimination half-life of darifenacin following chronic dosing is approximately 13-19 hours.

Toxicity Values

Not Available

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

No indication of carcinogenicity to humans (not listed by IARC).

Uses/Sources

For the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency.

Minimum Risk Level

Not Available

Health Effects

Not Available

Symptoms

Overdosage can potentially result in severe central anticholinergic effects.

Treatment

Not Available

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

Not Available

UniProt ID

Not Available

OMIM ID

ChEBI ID

391960

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Darifenacin

PDB ID

Not Available

ACToR ID

Not Available

Wikipedia Link

Darifenacin

References

Synthesis Reference

Valeriano Merli, Augusto Canavesi, Paola Daverio, “Processes for preparing darifenacin hydrobromide.” U.S. Patent US20070197631, issued August 23, 2007.

MSDS

Not Available

General References

Not Available

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not Available

Targets

Target Details

1. Muscarinic acetylcholine receptor M2

General Function:: G-protein coupled acetylcholine receptor activity
Specific Function:: 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. Signaling promotes phospholipase C activity, leading to the release of inositol trisphosphate (IP3); this then triggers calcium ion release into the cytosol.
Gene Name:: CHRM2
Uniprot ID:: P08172
Molecular Weight:: 51714.605 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.047 uM	Not Available	BindingDB 50109647
Inhibitory	0.05 uM	Not Available	BindingDB 50109647

References

Jha S, Parsons M: Treatment of overactive bladder in the aging population: focus on darifenacin. Clin Interv Aging. 2006;1(4):309-16. [18046909 ]
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. [10374898 ]
Hirose H, Aoki I, Kimura T, Fujikawa T, Numazawa T, Sasaki K, Sato A, Hasegawa T, Nishikibe M, Mitsuya M, Ohtake N, Mase T, Noguchi K: Pharmacological properties of (2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopen tyl]-2-hydroxy-2-phenylacetamide: a novel mucarinic antagonist with M(2)-sparing antagonistic activity. J Pharmacol Exp Ther. 2001 May;297(2):790-7. [11303071 ]
Sagara Y, Sagara T, Mase T, Kimura T, Numazawa T, Fujikawa T, Noguchi K, Ohtake N: Cyclohexylmethylpiperidinyltriphenylpropioamide: a selective muscarinic M(3) antagonist discriminating against the other receptor subtypes. J Med Chem. 2002 Feb 14;45(4):984-7. [11831911 ]
Starck JP, Talaga P, Quere L, Collart P, Christophe B, Lo Brutto P, Jadot S, Chimmanamada D, Zanda M, Wagner A, Mioskowski C, Massingham R, Guyaux M: Potent anti-muscarinic activity in a novel series of quinuclidine derivatives. Bioorg Med Chem Lett. 2006 Jan 15;16(2):373-7. Epub 2005 Nov 3. [16275087 ]
Nelson CP, Gupta P, Napier CM, Nahorski SR, Challiss RA: Functional selectivity of muscarinic receptor antagonists for inhibition of M3-mediated phosphoinositide responses in guinea pig urinary bladder and submandibular salivary gland. J Pharmacol Exp Ther. 2004 Sep;310(3):1255-65. Epub 2004 May 12. [15140916 ]

Target Details

2. Muscarinic acetylcholine receptor M1

General Function:: Phosphatidylinositol phospholipase c activity
Specific Function:: 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.
Gene Name:: CHRM1
Uniprot ID:: P11229
Molecular Weight:: 51420.375 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.0055 uM	Not Available	BindingDB 50109647

References

Jha S, Parsons M: Treatment of overactive bladder in the aging population: focus on darifenacin. Clin Interv Aging. 2006;1(4):309-16. [18046909 ]
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. [10374898 ]
Hirose H, Aoki I, Kimura T, Fujikawa T, Numazawa T, Sasaki K, Sato A, Hasegawa T, Nishikibe M, Mitsuya M, Ohtake N, Mase T, Noguchi K: Pharmacological properties of (2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopen tyl]-2-hydroxy-2-phenylacetamide: a novel mucarinic antagonist with M(2)-sparing antagonistic activity. J Pharmacol Exp Ther. 2001 May;297(2):790-7. [11303071 ]
Sagara Y, Sagara T, Mase T, Kimura T, Numazawa T, Fujikawa T, Noguchi K, Ohtake N: Cyclohexylmethylpiperidinyltriphenylpropioamide: a selective muscarinic M(3) antagonist discriminating against the other receptor subtypes. J Med Chem. 2002 Feb 14;45(4):984-7. [11831911 ]

Target Details

3. Muscarinic acetylcholine receptor M3

General Function:: Receptor activity
Specific Function:: 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.
Gene Name:: CHRM3
Uniprot ID:: P20309
Molecular Weight:: 66127.445 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.00084 uM	Not Available	BindingDB 50109647
Inhibitory	0.0013 uM	Not Available	BindingDB 50109647

References

Hirose H, Aoki I, Kimura T, Fujikawa T, Numazawa T, Sasaki K, Sato A, Hasegawa T, Nishikibe M, Mitsuya M, Ohtake N, Mase T, Noguchi K: Pharmacological properties of (2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopen tyl]-2-hydroxy-2-phenylacetamide: a novel mucarinic antagonist with M(2)-sparing antagonistic activity. J Pharmacol Exp Ther. 2001 May;297(2):790-7. [11303071 ]
Sagara Y, Sagara T, Mase T, Kimura T, Numazawa T, Fujikawa T, Noguchi K, Ohtake N: Cyclohexylmethylpiperidinyltriphenylpropioamide: a selective muscarinic M(3) antagonist discriminating against the other receptor subtypes. J Med Chem. 2002 Feb 14;45(4):984-7. [11831911 ]
Starck JP, Talaga P, Quere L, Collart P, Christophe B, Lo Brutto P, Jadot S, Chimmanamada D, Zanda M, Wagner A, Mioskowski C, Massingham R, Guyaux M: Potent anti-muscarinic activity in a novel series of quinuclidine derivatives. Bioorg Med Chem Lett. 2006 Jan 15;16(2):373-7. Epub 2005 Nov 3. [16275087 ]
Nelson CP, Gupta P, Napier CM, Nahorski SR, Challiss RA: Functional selectivity of muscarinic receptor antagonists for inhibition of M3-mediated phosphoinositide responses in guinea pig urinary bladder and submandibular salivary gland. J Pharmacol Exp Ther. 2004 Sep;310(3):1255-65. Epub 2004 May 12. [15140916 ]

Target Details

4. Muscarinic acetylcholine receptor M4

General Function:: Guanyl-nucleotide exchange factor activity
Specific Function:: 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.
Gene Name:: CHRM4
Uniprot ID:: P08173
Molecular Weight:: 53048.65 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.0086 uM	Not Available	BindingDB 50109647

References

Jha S, Parsons M: Treatment of overactive bladder in the aging population: focus on darifenacin. Clin Interv Aging. 2006;1(4):309-16. [18046909 ]
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. [10374898 ]
Hirose H, Aoki I, Kimura T, Fujikawa T, Numazawa T, Sasaki K, Sato A, Hasegawa T, Nishikibe M, Mitsuya M, Ohtake N, Mase T, Noguchi K: Pharmacological properties of (2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopen tyl]-2-hydroxy-2-phenylacetamide: a novel mucarinic antagonist with M(2)-sparing antagonistic activity. J Pharmacol Exp Ther. 2001 May;297(2):790-7. [11303071 ]
Sagara Y, Sagara T, Mase T, Kimura T, Numazawa T, Fujikawa T, Noguchi K, Ohtake N: Cyclohexylmethylpiperidinyltriphenylpropioamide: a selective muscarinic M(3) antagonist discriminating against the other receptor subtypes. J Med Chem. 2002 Feb 14;45(4):984-7. [11831911 ]

Target Details

5. Muscarinic acetylcholine receptor M5

General Function:: Phosphatidylinositol phospholipase c activity
Specific Function:: 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.
Gene Name:: CHRM5
Uniprot ID:: P08912
Molecular Weight:: 60073.205 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.0023 uM	Not Available	BindingDB 50109647

References

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. [10374898 ]
Jha S, Parsons M: Treatment of overactive bladder in the aging population: focus on darifenacin. Clin Interv Aging. 2006;1(4):309-16. [18046909 ]
Sagara Y, Sagara T, Mase T, Kimura T, Numazawa T, Fujikawa T, Noguchi K, Ohtake N: Cyclohexylmethylpiperidinyltriphenylpropioamide: a selective muscarinic M(3) antagonist discriminating against the other receptor subtypes. J Med Chem. 2002 Feb 14;45(4):984-7. [11831911 ]

Darifenacin (T3D3499)

Structure for T3D3499: Darifenacin

Targets

Binding/Activity Constants

References

Binding/Activity Constants

References

Binding/Activity Constants

References

Binding/Activity Constants

References

Binding/Activity Constants

References