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Showing drug card for Darifenacin (DB00496)

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Version 2.5
Creation Date 2005-06-13 13:24:05
Update Date 2009-06-23 18:06:48
Primary Accession Number DB00496
Secondary Accession Number
  • APRD00903
Name Darifenacin
Drug Type
  • Approved
  • Investigational
  • 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.
Synonyms
  1. darifenacin
Brand Names
  1. Emselex
  2. Enablex
Brand Mixtures Not Available
Chemical IUPAC Name 2-[(3S)-1-[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]pyrrolidin-3-yl]-2,2-di(phenyl)acetamide
Chemical Formula C28H30N2O2
Chemical Structure Structure
CAS Registry Number 133099-04-4
InChI Identifier InChI=1/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/f/h29H2
InChI Key HXGBXQDTNZMWGS-WOPQRDCQDH
KEGG Drug D01699 Link Image
KEGG Compound Not Available
PubChem Compound 444031 Link Image
PubChem Substance 7979027 Link Image
ChEBI ID Not Available
PharmGKB ID Not Available
HET ID Not Available
GenBank ID Not Available
Drug ID Number [DIN] Not Available
RxList Link http://www.rxlist.com/cgi/generic3/enablex.htm Link Image
PDRhealth Link Not Available
Wikipedia Link http://en.wikipedia.org/wiki/Darifenacin Link Image
FDA Label
Material Safety Data Sheet (MSDS) Not Available
Synthesis Reference Not Available
Average Molecular Weight 426.5500
Monoisotopic Molecular Weight 426.2307
State Solid
Melting Point Not Available
Experimental Water Solubility Not Available Source: PhysProp
Predicted Water Solubility 2.98e-04 mg/mL Calculated using ALOGPS
Experimental LogP/Hydrophobicity 4.5 Source: PhysProp
Predicted LogP 4.35 Calculated using ALOGPS
Experimental LogS Not Available
Predicted LogS -6.16 Calculated using ALOGPS
Experimental Caco2 Permeability Not Available
pKa/Isoelectric Point Not Available
Mass Spectrum Not Available
MOL File Show Link Image | Download Link Image
SDF File Show Link Image | Download Link Image
PDB File Show Link Image | Download Link Image
2D Structure
3D Structure
Experimental PDB ID Not Available
Isomeric SMILES NC(=O)C([C@@H]1CCN(CCC2=CC3=C(OCC3)C=C2)C1)(C1=CC=CC=C1)C1=CC=CC=C1
Canonical SMILES NC(=O)C(C1CCN(CCC2=CC3=C(OCC3)C=C2)C1)(C1=CC=CC=C1)C1=CC=CC=C1
Drug Category
  • Muscarinic Antagonists
  • Urinary antispasmodics
ATC Codes
AHFS Codes
  • 86:12.00
Indication For the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency.
Pharmacology 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.
Toxicity Overdosage can potentially result in severe central anticholinergic effects.
Protein Binding Darifenacin is approximately 98% bound to plasma proteins (primarily to alpha-1-acid-glycoprotein).
Biotransformation 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.
Dosage Forms
Form Route
Tablet, extended release Oral
Patient Information Show Link Image
Contraindications Show Link Image
Interactions Show Link Image
Drug Interactions
Drug Interaction
Clarithromycin This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism
Donepezil Possible antagonism of action
Galantamine Possible antagonism of action
Itraconazole This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism
Ketoconazole This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism
Nefazodone This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism
Nelfinavir This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism
Ritonavir This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism
Rivastigmine Possible antagonism of action
Food Interactions
  • Take without regard to meals.
Pathways Not Available
General References
  1. Wikipedia Link Image
  2. RxList Link Image
Organisms Affected
  • Humans and other mammals
Phase 1 Metabolizing Enzymes
  1. Cytochrome P450 3A4 (CYP3A4)
  2. Cytochrome P450 2D6 (CYP2D6)
Targets
  1. Muscarinic acetylcholine receptor M3
Phase 1 Metabolizing Enzyme 1 [top]
Enzyme 1 Name Cytochrome P450 3A4 (CYP3A4)
Enzyme 1 Gene Name CYP3A4
Enzyme 1 SwissProt ID P08684 Link Image
Enzyme 1 SNPs SNPJam Report Link Image
Enzyme 1 Protein Sequence >sp|P08684|CP3A4_HUMAN Cytochrome P450 3A4 (EC 1.14.13.67) 
ALIPDLAMETWLLLAVSLVLLYLYGTHSHGLFKKLGIPGPTPLPFLGNILSYHKGFCMFD
MECHKKYGKVWGFYDGQQPVLAITDPDMIKTVLVKECYSVFTNRRPFGPVGFMKSAISIA
EDEEWKRLRSLLSPTFTSGKLKEMVPIIAQYGDVLVRNLRREAETGKPVTLKDVFGAYSM
DVITSTSFGVNIDSLNNPQDPFVENTKKLLRFDFLDPFFLSITVFPFLIPILEVLNICVF
PREVTNFLRKSVKRMKESRLEDTQKHRVDFLQLMIDSQNSKETESHKALSDLELVAQSII
FIFAGYETTSSVLSFIMYELATHPDVQQKLQEEIDAVLPNKAPPTYDTVLQMEYLDMVVN
ETLRLFPIAMRLERVCKKDVEINGMFIPKGWVVMIPSYALHRDPKYWTEPEKFLPERFSK
KNKDNIDPYIYTPFGSGPRNCIGMRFALMNMKLALIRVLQNFSFKPCKETQIPLKLSLGG
LLQPEKPVVLKVESRDGTVSGA
Phase 1 Metabolizing Enzyme 2 [top]
Enzyme 2 Name Cytochrome P450 2D6 (CYP2D6)
Enzyme 2 Gene Name CYP2D6
Enzyme 2 SwissProt ID P10635 Link Image
Enzyme 2 SNPs SNPJam Report Link Image
Enzyme 2 Protein Sequence >sp|P10635|CP2D6_HUMAN Cytochrome P450 2D6 (EC 1.14.14.1) 
MGLEALVPLAVIVAIFLLLVDLMHRRQRWAARYPPGPLPLPGLGNLLHVDFQNTPYCFDQ
LRRRFGDVFSLQLAWTPVVVLNGLAAVREALVTHGEDTADRPPVPITQILGFGPRSQGVF
LARYGPAWREQRRFSVSTLRNLGLGKKSLEQWVTEEAACLCAAFANHSGRPFRPNGLLDK
AVSNVIASLTCGRRFEYDDPRFLRLLDLAQEGLKEESGFLREVLNAVPVLLHIPALAGKV
LRFQKAFLTQLDELLTEHRMTWDPAQPPRDLTEAFLAEMEKAKGNPESSFNDENLRIVVA
DLFSAGMVTTSTTLAWGLLLMILHPDVQRRVQQEIDDVIGQVRRPEMGDQAHMPYTTAVI
HEVQRFGDIVPLGMTHMTSRDIEVQGFRIPKGTTLITNLSSVLKDEAVWEKPFRFHPEHF
LDAQGHFVKPEAFLPFSAGRRACLGEPLARMELFLFFTSLLQHFSFSVPTGQPRPSHHGV
FAFLVSPSPYELCAVPR
Drug Target 1 [top]
Target 1 ID 51
Target 1 Name Muscarinic acetylcholine receptor M3
Target 1 Synonyms Not Available
Target 1 Gene Name CHRM3
Target 1 Protein Sequence >Muscarinic acetylcholine receptor M3 
MTLHNNSTTSPLFPNISSSWIHSPSDAGLPPGTVTHFGSYNVSRAAGNFSSPDGTTDDPL
GGHTVWQVVFIAFLTGILALVTIIGNILVIVSFKVNKQLKTVNNYFLLSLACADLIIGVI
SMNLFTTYIIMNRWALGNLACDLWLAIDYVASNASVMNLLVISFDRYFSITRPLTYRAKR
TTKRAGVMIGLAWVISFVLWAPAILFWQYFVGKRTVPPGECFIQFLSEPTITFGTAIAAF
YMPVTIMTILYWRIYKETEKRTKELAGLQASGTEAETENFVHPTGSSRSCSSYELQQQSM
KRSNRRKYGRCHFWFTTKSWKPSSEQMDQDHSSSDSWNNNDAAASLENSASSDEEDIGSE
TRAIYSIVLKLPGHSTILNSTKLPSSDNLQVPEEELGMVDLERKADKLQAQKSVDDGGSF
PKSFSKLPIQLESAVDTAKTSDVNSSVGKSTATLPLSFKEATLAKRFALKTRSQITKRKR
MSLVKEKKAAQTLSAILLAFIITWTPYNIMVLVNTFCDSCIPKTFWNLGYWLCYINSTVN
PVCYALCNKTFRTTFKMLLLCQCDKKKRRKQQYQQRQSVIFHKRAPEQAL
Target 1 Number of Residues 599
Target 1 Molecular Weight 66129
Target 1 Theoretical pI 9.62
Target 1 GO Classification
Function
amine receptor activity
muscarinic acetylcholine receptor activity
signal transducer activity
receptor activity
transmembrane receptor activity
G-protein coupled receptor activity
rhodopsin-like receptor activity
Process
cellular process
cell communication
signal transduction
cell surface receptor linked signal transduction
G-protein coupled receptor protein signaling pathway
Component
cell
membrane
intrinsic to membrane
integral to membrane
Target 1 General Function Involved in rhodopsin-like receptor activity
Target 1 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
Target 1 Pathways Not Available
Target 1 Reactions Not Available
Target 1 Pfam Domain Function
Target 1 Signals
  • None
Target 1 Transmembrane Regions
  • 68-91
  • 105-125
  • 143-164
  • 185-207
  • 230-252
  • 493-513
  • 528-547
Target 1 Essentiality Non-Essential
Target 1 GenBank ID Protein 32324 Link Image
Target 1 UniProtKB/Swiss-Prot ID P20309 Link Image
Target 1 UniProtKB/Swiss-Prot Entry Name ACM3_HUMAN Link Image
Target 1 PDB ID Not Available
Target 1 Cellular Location
  • Membrane
  • multi-pass membrane protein
Target 1 Gene Sequence >1773 bp 
ATGACCTTGCACAATAACAGTACAACCTCGCCTTTGTTTCCAAACATCAGCTCCTCCTGG
ATACACAGCCCCTCCGATGCAGGGCTGCCCCCGGGAACCGTCACTCATTTCGGCAGCTAC
AATGTTTCTCGAGCAGCTGGCAATTTCTCCTCTCCAGACGGTACCACCGATGACCCTCTG
GGAGGTCATACCGTCTGGCAAGTGGTCTTCATCGCTTTCTTAACGGGCATCCTGGCCTTG
GTGACCATCATCGGCAACATCCTGGTAATTGTGTCATTTAAGGTCAACAAGCAGCTGAAG
ACGGTCAACAACTACTTCCTCTTAAGCCTGGCCTGTGCCGATCTGATTATCGGGGTCATT
TCAATGAATCTGTTTACGACCTACATCATCATGAATCGATGGGCCTTAGGGAACTTGGCC
TGTGACCTCTGGCTTGCCATTGACTACGTAGCCAGCAATGCCTCTGTTATGAATCTTCTG
GTCATCAGCTTTGACAGATACTTTTCCATCACGAGGCCGCTCACGTACCGAGCCAAACGA
ACAACAAAGAGAGCCGGTGTGATGATCGGTCTGGCTTGGGTCATCTCCTTTGTCCTTTGG
GCTCCTGCCATCTTGTTCTGGCAATACTTTGTTGGAAAGAGAACTGTGCCTCCGGGAGAG
TGCTTCATTCAGTTCCTCAGTGAGCCCACCATTACTTTTGGCACAGCCATCGCTGCTTTT
TATATGCCTGTCACCATTATGACTATTTTATACTGGAGGATCTATAAGGAAACTGAAAAG
CGTACCAAAGAGCTTGCTGGCCTGCAAGCCTCTGGGACAGAGGCAGAGACAGAAAACTTT
GTCCACCCCACGGGCAGTTCTCGAAGCTGCAGCAGTTACGAACTTCAACAGCAAAGCATG
AAACGCTCCAACAGGAGGAAGTATGGCCGCTGCCACTTCTGGTTCACAACCAAGAGCTGG
AAACCCAGCTCCGAGCAGATGGACCAAGACCACAGCAGCAGTGACAGTTGGAACAACAAT
GATGCTGCTGCCTCCCTGGAGAACTCCGCCTCCTCCGACGAGGAGGACATTGGCTCCGAG
ACGAGAGCCATCTACTCCATCGTGCTCAAGCTTCCGGGTCACAGCACCATCCTCAACTCC
ACCAAGTTACCCTCATCGGACAACCTGCAGGTGCCTGAGGAGGAGCTGGGGATGGTGGAC
TTGGAGAGGAAAGCCGACAAGCTGCAGGCCCAGAAGAGCGTGGACGATGGAGGCAGTTTT
CCAAAAAGCTTCTCCAAGCTTCCCATCCAGCTAGAGTCAGCCGTGGACACAGCTAAGACT
TCTGACGTCAACTCCTCAGTGGGTAAGAGCACGGCCACTCTACCTCTGTCCTTCAAGGAA
GCCACTCTGGCCAAGAGGTTTGCTCTGAAGACCAGAAGTCAGATCACTAAGCGGAAAAGG
ATGTCCCTGGTCAAGGAGAAGAAAGCGGCCCAGACCCTCAGTGCGATCTTGCTTGCCTTC
ATCATCACTTGGACCCCATACAACATCATGGTTCTGGTGAACACCTTTTGTGACAGCTGC
ATACCCAAAACCTTTTGGAATCTGGGCTACTGGCTGTGCTACATCAACAGCACCGTGAAC
CCCGTGTGCTATGCTCTGTGCAACAAAACATTCAGAACCACTTTCAAGATGCTGCTGCTG
TGCCAGTGTGACAAAAAAAAGAGGCGCAAGCAGCAGTACCAGCAGAGACAGTCGGTCATT
TTTCACAAGCGCGCACCCGAGCAGGCCTTGTAG
Target 1 GenBank Gene ID
Target 1 GeneCard ID CHRM3 Link Image
Target 1 GenAtlas ID CHRM3 Link Image
Target 1 HGNC ID HGNC:1952 Link Image
Target 1 Chromosome Location 1
Target 1 Locus 1q43
Target 1 SNPs SNPJam Report Link Image
Target 1 General References
  1. Speek M: Antisense promoter of human L1 retrotransposon drives transcription of adjacent cellular genes. Mol Cell Biol. 2001 Mar;21(6):1973-85. [PubMed Link Image]
  2. Bonner TI, Young AC, Brann MR, Buckley NJ: Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes. Neuron. 1988 Jul;1(5):403-10. [PubMed Link Image]
  3. Peralta EG, Ashkenazi A, Winslow JW, Smith DH, Ramachandran J, Capon DJ: Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors. EMBO J. 1987 Dec 20;6(13):3923-9. [PubMed Link Image]
Target 1 Drug References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed Link Image]

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.