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=CC3=C(OCC3)C=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 160 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 2849		0.33 nM [Kd]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Overactive bladder 39 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021513s010lbl.pdf	Palliative		Approved 8583	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	unhealthy, 57.6 Health Status: unhealthy Age Group: 57.6 Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf	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
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	unhealthy, 57.6 Health Status: unhealthy Age Group: 57.6 Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf	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

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	unhealthy, 57.6 Health Status: unhealthy Age Group: 57.6 Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf
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	unhealthy, 57.6 Health Status: unhealthy Age Group: 57.6 Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf
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	unhealthy, 57.6 Health Status: unhealthy Age Group: 57.6 Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf
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	unhealthy, 57.6 Health Status: unhealthy Age Group: 57.6 Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex_biopharmr.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946 inhibitor 2252	inhibitor 2438	substrate 1388 inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 2153	P-gp 2052 BCRP 697 MRP 9

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP1A2 2333	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021513lbl.pdf@page=6 Page: 6.0	no
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021513lbl.pdf@page=6 Page: 6.0	no
CYP2D6 2546	inhibitor 4027 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 2633	inhibitor 4027 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 1388	substrate 4014 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 1946	substrate 4014 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 697	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/21826715/	unresponsive
MRP 9	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/21826715/	unresponsive
P-gp 2052	substrate 4014 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1002/nau.21110	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 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
Effects of YM905, a novel muscarinic M3-receptor antagonist, on experimental models of bowel dysfunction in vivo.	2001 Jul	11488427
Molecular and pharmacological characterization of muscarinic receptor subtypes in a rat parotid gland cell line: comparison with native parotid gland.	2001 May	11303063
M(3) receptor antagonism by the novel antimuscarinic agent solifenacin in the urinary bladder and salivary gland.	2002 Aug	12122494
Irritable bowel syndrome neuropharmacology. A review of approved and investigational compounds.	2002 Jul	12184141
Model of rapid gastrointestinal transit in dogs: effects of muscarinic antagonists and a nitric oxide synthase inhibitor.	2002 Oct	12358682
The subtypes of muscarinic receptors for neurogenic bladder contraction in rats.	2002 Oct 4	12354576
Effect of extrinsic denervation on muscarinic neurotransmission in the canine ileocolonic region.	2003 Apr	12680916
Pharmacological effects of darifenacin on human isolated urinary bladder.	2003 Dec	14624061
Demonstration of functional M3-muscarinic receptors in ventricular cardiomyocytes of adult rats.	2003 Jan	12522085
Receptor signaling mechanisms underlying muscarinic agonist-evoked contraction in guinea-pig ileal longitudinal smooth muscle.	2003 May	12770939
[The medical treatment of overactive bladder].	2003 May	12746713
Gender comparison of muscarinic receptor expression and function in rat and human urinary bladder: differential regulation of M2 and M3 receptors?	2003 May	12669188
Darifenacin: in the treatment of overactive bladder.	2004	15493952
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
Comparison of in vitro selectivity profiles of solifenacin succinate (YM905) and current antimuscarinic drugs in bladder and salivary glands: a Ca2+ mobilization study in monkey cells.	2004 Jan 2	14659973
Role of antimuscarinics in the treatment of nonneurogenic daytime urinary incontinence in children.	2004 Mar	15013652
Gateways to clinical trials.	2004 Nov	15632957
Mechanisms mediating cholinergic antral circular smooth muscle contraction in rats.	2004 Nov 15	15484303
Elevating our therapeutic expectations in overactive bladder.	2004 Oct	15543927
The emerging role of solifenacin in the treatment of overactive bladder.	2004 Oct	15461562
Overactive bladder in the elderly: a guide to pharmacological management.	2005	16363885
Darifenacin in the treatment of overactive bladder.	2005 Jul	16193097
Comparison of darifenacin and oxybutynin in patients with overactive bladder: assessment of ambulatory urodynamics and impact on salivary flow.	2005 Jul	15936869
Gateways to clinical trials.	2005 Jun	16082422
New treatment options for overactive bladder.	2005 Jun	16050656
Darifenacin: another antimuscarinic for overactive bladder.	2005 May	16548640
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 Oct	16273137
Urodynamic effects of oxybutynin and tolterodine in conscious and anesthetized rats under different cystometrographic conditions.	2005 Oct 11	16216132
Role of muscarinic receptor antagonists in urgency and nocturia.	2005 Sep	16083453
The clinical pharmacokinetics of darifenacin.	2006	16584282
Practical considerations of new drugs: new choices for old problems.	2006 Apr	16669748
The causes and consequences of overactive bladder.	2006 Apr	16620184
Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects.	2006 Aug	16687205
In vivo demonstration of M3 muscarinic receptor subtype selectivity of darifenacin in mice.	2006 Dec 14	16996089
Muscarinic receptors in the bladder: from basic research to therapeutics.	2006 Feb	16465186
New drugs 06, part I.	2006 Feb	16462265
M2 and M3 muscarinic receptor activation of urinary bladder contractile signal transduction. I. Normal rat bladder.	2006 Feb	16243961
Efficacy, tolerability and safety of darifenacin, an M(3) selective receptor antagonist: an investigation of warning time in patients with OAB.	2006 Jan	16409440
Human muscarinic receptor binding characteristics of antimuscarinic agents to treat overactive bladder.	2006 Jan	16406943
Constitutive activity and inverse agonism at the M2 muscarinic acetylcholine receptor.	2006 Jan	16188951
Regulation of bladder muscarinic receptor subtypes by experimental pathologies.	2006 Jul	16879497
[Oral anticholinergics in overactive bladder].	2006 Jul	16791627
[Anticholinergics for overactive bladder: does subtype selectivity play a role?].	2006 Jul	16767455
Gateways to clinical trials.	2006 Mar	16636723
Management of overactive bladder and urge urinary incontinence in the elderly patient.	2006 Mar	16483866
Treatment of the overactive bladder syndrome with muscarinic receptor antagonists: a matter of metabolites?	2006 Nov	17021853
Darifenacin: Pharmacology and clinical usage.	2006 Nov	17011383
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

UK-88525

Preferred Name

English

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

UK88525

Code

English

DARIFENACIN [USAN]

Common Name

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