DARIFENACIN

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C28H30N2O2
Molecular Weight	426.55
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC(=O)C([C@@H]1CCN(CCC2=CC=C3OCCC3=C2)C1)(C4=CC=CC=C4)C5=CC=CC=C5

InChI

InChIKey=HXGBXQDTNZMWGS-RUZDIDTESA-N

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

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021513s010lbl.pdf
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/9121347

Darifenacin is a selective muscarinic receptor M3 antagonist which was approved by FDA for the treatment of overactive bladder.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Muscarinic acetylcholine receptor M3 159 Target ID: P20309 Gene ID: 1131.0 Gene Symbol: CHRM3 Target Organism: Homo sapiens (Human) Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021513s010lbl.pdf	Antagonist 2778		0.33 nM [Kd]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Overactive bladder 38 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021513s010lbl.pdf	Palliative		Approved 8429	ENABLEX Approved Use ENABLEX® (darifenacin) extended-release tablets are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency. Launch Date 2004

C_max

Value	Dose	Co-administered	Analyte	Population
2.01 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021513s010lbl.pdf	7.5 mg 1 times / day steady-state, oral dose: 7.5 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		DARIFENACIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
5.76 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021513s010lbl.pdf	15 mg 1 times / day steady-state, oral dose: 15 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		DARIFENACIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
29.24 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021513s010lbl.pdf	7.5 mg 1 times / day steady-state, oral dose: 7.5 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		DARIFENACIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
88.9 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021513s010lbl.pdf	15 mg 1 times / day steady-state, oral dose: 15 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		DARIFENACIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
12.43 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021513s010lbl.pdf	7.5 mg 1 times / day steady-state, oral dose: 7.5 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		DARIFENACIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
12.05 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021513s010lbl.pdf	15 mg 1 times / day steady-state, oral dose: 15 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		DARIFENACIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
2% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021513s010lbl.pdf	7.5 mg 1 times / day steady-state, oral dose: 7.5 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		DARIFENACIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021513s010lbl.pdf	15 mg 1 times / day steady-state, oral dose: 15 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		DARIFENACIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
15 mg 1 times / day multiple, oral Recommended Dose: 15 mg, 1 times / day Route: oral Route: multiple Dose: 15 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf Page: 1041	unhealthy, 57.6 n = 337 Health Status: unhealthy Condition: overactive bladder Age Group: 57.6 Sex: M+F Population Size: 337 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf Page: 1041	Disc. AE: Constipation, Dry mouth... AEs leading to discontinuation/dose reduction: Constipation (1%) Dry mouth (1%) Nervous system disorder NOS (0.6%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf Page: 1041
7.5 mg 1 times / day multiple, oral Recommended Dose: 7.5 mg, 1 times / day Route: oral Route: multiple Dose: 7.5 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf Page: 1041	unhealthy, 57.6 n = 561 Health Status: unhealthy Condition: overactive bladder Age Group: 57.6 Sex: M+F Population Size: 561 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf Page: 1041	Disc. AE: Heart block AV second degree... AEs leading to discontinuation/dose reduction: Heart block AV second degree (0.3%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf Page: 1041

AEs

AE	Significance	Dose	Population
Nervous system disorder NOS	0.6% Disc. AE	15 mg 1 times / day multiple, oral Recommended Dose: 15 mg, 1 times / day Route: oral Route: multiple Dose: 15 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf Page: 1041	unhealthy, 57.6 n = 337 Health Status: unhealthy Condition: overactive bladder Age Group: 57.6 Sex: M+F Population Size: 337 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf Page: 1041
Constipation	1% Disc. AE	15 mg 1 times / day multiple, oral Recommended Dose: 15 mg, 1 times / day Route: oral Route: multiple Dose: 15 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf Page: 1041	unhealthy, 57.6 n = 337 Health Status: unhealthy Condition: overactive bladder Age Group: 57.6 Sex: M+F Population Size: 337 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf Page: 1041
Dry mouth	1% Disc. AE	15 mg 1 times / day multiple, oral Recommended Dose: 15 mg, 1 times / day Route: oral Route: multiple Dose: 15 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf Page: 1041	unhealthy, 57.6 n = 337 Health Status: unhealthy Condition: overactive bladder Age Group: 57.6 Sex: M+F Population Size: 337 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf Page: 1041
Heart block AV second degree	0.3% Disc. AE	7.5 mg 1 times / day multiple, oral Recommended Dose: 7.5 mg, 1 times / day Route: oral Route: multiple Dose: 7.5 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf Page: 1041	unhealthy, 57.6 n = 561 Health Status: unhealthy Condition: overactive bladder Age Group: 57.6 Sex: M+F Population Size: 561 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf Page: 1041

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587	inhibitor 1767	substrate 1217 inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524	P-gp 1537 BCRP 561 MRP 7

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021513lbl.pdf@page=6 Page: 6.0	no
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021513lbl.pdf@page=6 Page: 6.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf@page=23 Page: 23.0	yes [IC50 2 uM]	yes (co-administration study) Comment: Label: Mean Cmax and AUC of imipramine, a CYP2D6 substrate, were increased 57% and 11 70%, respectively, in the presence of steady-state darifenacin; Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf@page=23 Page: 23.0
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf@page=23 Page: 23.0	yes [IC50 5 uM]	weak (co-administration study) Comment: Label: Darifenacin coadministered with a single oral dose of 15 midazolam 7.5 mg resulted in 17% increase in midazolam exposure Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf@page=23 Page: 23.0

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf#page=22 Page: 22.0	major	yes (co-administration study) Comment: Label: Darifenacin exposure following 30 mg once daily at steady state was 33% higher in the presence of the potent CYP2D6 inhibitor paroxetine; Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf#page=22 Page: 22.0
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf#page=46 Page: 46.0	major	yes (co-administration study) Comment: Label: Mean steady state darifenacin exposure in EM subjects was about 5 fold higher when ketoconazole was co-administered; mean Cmax and AUC of 25 darifenacin following 30 mg once daily dosing at steady state were 128% and 95% higher, 26 respectively, in the presence of erythromycin; Coadministration of fluconazole and darifenacin 30 mg once daily at steady state increased darifenacin Cmax and AUC by 88% and 84%, respectively Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf#page=46 Page: 46.0
BCRP 561	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/21826715/	unresponsive
MRP 7	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/21826715/	unresponsive
P-gp 1537	substrate 3367 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1002/nau.21110	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_pharmr.pdf#page=5 Page: 5.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:391960	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:391960
ChemicalBook	CB1506695	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB1506695
MolPort	MolPort-005-943-011	https://www.molport.com/shop/molecule-link/MolPort-005-943-011
ZINC	ZINC000001996117	http://zinc15.docking.org/substances/ZINC000001996117

PubMed

Title	Date	PubMed
Pharmacological characterization of muscarinic receptors in dog isolated ciliary and urinary bladder smooth muscle.	2001 Feb	11181424
Pharmacological properties of (2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide: a novel mucarinic antagonist with M(2)-sparing antagonistic activity.	2001 May	11303071
Molecular and pharmacological characterization of muscarinic receptor subtypes in a rat parotid gland cell line: comparison with native parotid gland.	2001 May	11303063
Population pharmacokinetic modelling of darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first-pass metabolism, CYP2D6 genotype and formulation-dependent bioavailability.	2003 Dec	14616424
Update on overactive bladder: pharmacologic approaches on the horizon.	2003 Oct	14499063
Drug treatment of overactive bladder: efficacy, cost and quality-of-life considerations.	2004	15257626
Darifenacin, an M3 selective receptor antagonist, is an effective and well-tolerated once-daily treatment for overactive bladder.	2004 Apr	15041104
Assessment of the relative in vivo potency of the hydroxylated metabolite of darifenacin in its ability to decrease salivary flow using pooled population pharmacokinetic-pharmacodynamic data.	2004 Feb	14748816
Role of antimuscarinics in the treatment of nonneurogenic daytime urinary incontinence in children.	2004 Mar	15013652
The M2 muscarinic receptor mediates in vitro bladder contractions from patients with neurogenic bladder dysfunction.	2004 May	14751843
Gateways to clinical trials.	2004 Nov	15632957
Elevating our therapeutic expectations in overactive bladder.	2004 Oct	15543927
Solifenacin in overactive bladder syndrome.	2005	16363887
[Overactive bladder].	2005	15912847
Muscarinic receptor subtypes in human bladder detrusor and mucosa, studied by radioligand binding and quantitative competitive RT-PCR: changes in ageing.	2005 Apr	15723094
Gateways to clinical trials.	2005 Jan-Feb	15834459
Effects of ageing on muscarinic receptor subtypes and function in rat urinary bladder.	2005 Jul	16059734
Darifenacin in the treatment of overactive bladder.	2005 Jul	15963212
A role for muscarinic receptors or rho-kinase in hypertension associated rat bladder dysfunction?	2005 Jun	15879883
Pharmacodynamic effects of darifenacin, a muscarinic M selective receptor antagonist for the treatment of overactive bladder, in healthy volunteers.	2005 Nov	16225528
Gateways to clinical trials.	2005 Sep	16258596
The clinical pharmacokinetics of darifenacin.	2006	16584282
Efficacy, tolerability and safety of darifenacin, an M(3) selective receptor antagonist: an investigation of warning time in patients with OAB.	2006 Jan	16409440
Constitutive activity and inverse agonism at the M2 muscarinic acetylcholine receptor.	2006 Jan	16188951
Gateways to clinical trials.	2006 Jan-Feb	16541195
[Oral anticholinergics in overactive bladder].	2006 Jul	16791627
Gateways to clinical trials.	2006 Mar	16636723
Treatment of the overactive bladder syndrome with muscarinic receptor antagonists: a matter of metabolites?	2006 Nov	17021853
Long-term treatment with darifenacin for overactive bladder: results of a 2-year, open-label extension study.	2006 Nov	16879437
Public Relations: Ketchum brands new product with innovative PR strategy.	2006 Sep-Oct	17048759

Patents

Sample Use Guides

In Vivo Use Guide

The recommended starting dose of darifenacin extended-release tablets (Enablex) is 7.5 mg once daily.

Route of Administration: Oral

In Vitro Use Guide

Bladder smooth muscle and submandibular gland cells isolated from Cynomolgus monkeys were treated with darifenacin and pKi values obtained in Ca2+ mobilization assay were 8,4 and 8,8, respectively.

Name

Type

Language

DARIFENACIN

Official Name

English

3-PYRROLIDINEACETAMIDE, 1-(2-(2,3-DIHYDRO-5-BENZOFURANYL)ETHYL)-.ALPHA.,.ALPHA.-DIPHENYL-, (3S)-

Systematic Name

English

darifenacin [INN]

Common Name

English

2-((3S)-1-(2-(2,3-DIHYDROBENZOFURAN-5-YL)ETHYL)PYRROLIDIN-3-YL)-2,2-DIPHENYLACETAMIDE.

Common Name

English

DARIFENACIN [VANDF]

Common Name

English

Darifenacin [WHO-DD]

Common Name

English

DARIFENACIN [USAN]

Common Name

English

UK-88525

Code

English

DARIFENACIN [MART.]

Common Name

English

DARIFENACIN EXTENDED RELEASE

Common Name

English

DARIFENACIN [MI]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C29704