Identification

Name
Imidafenacin
Accession Number
DB09262
Type
Small Molecule
Groups
Approved, Investigational
Description

Imidafenacin is a urinary antispasmodic of the anticholinergic class. It antagonizes mucarinic receptors in the bladder to reduce the frequency of urination in the treatment of overactive bladder. It is marketed in Japan under the tradenames Staybla by Ono Pharmaceutical and Uritos by Kyojin Pharmaceutical.

Structure
Thumb
Synonyms
Not Available
External IDs
KRP-197 / KRP-1979 / Ono-8025
International/Other Brands
Staybla (Ono Pharmaceutical) / Uritos (Kyorin Pharmaceutical)
Categories
UNII
XJR8Y07LJO
CAS number
170105-16-5
Weight
Average: 319.408
Monoisotopic: 319.168462308
Chemical Formula
C20H21N3O
InChI Key
SQKXYSGRELMAAU-UHFFFAOYSA-N
InChI
InChI=1S/C20H21N3O/c1-16-22-13-15-23(16)14-12-20(19(21)24,17-8-4-2-5-9-17)18-10-6-3-7-11-18/h2-11,13,15H,12,14H2,1H3,(H2,21,24)
IUPAC Name
4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide
SMILES
CC1=NC=CN1CCC(C(N)=O)(C1=CC=CC=C1)C1=CC=CC=C1

Pharmacology

Indication

Used in the treatment of overactive bladder [Label].

Pharmacodynamics

Imidafenacin is an antimuscarinic agent which acts to reduce the frequency of urination in patients with overactive bladder [Label].

Mechanism of action

Imidafenacin binds to and antagonizes muscarinic M1 and M3 receptors with high affinity [3]. It also antagonizes muscarinic M2 receptors but with lower affinity. M3 receptors stimulate contraction of the detrusor muscle in the bladder via release of calcium from the sarcoplasmic reticulum [4]. M2 receptors are also present in the detrusor muscle but serve to inhibit adenylate cyclase which reduces the relaxation mediated by β adrenergic receptors. Finally, M1 receptors are present on the parasympathetic neurons which release acetylcholine in the bladder. They act as an autocrine positive feedback loop and further increase release of acetylcholine. Antagonism of these receptors by imidafenacin prevents contraction of the bladder's detrusor muscle, prevents inhibition of the relation produced by sympathetic tone, and reduces acetylcholine release. Together these reduce the frequency of urination.

TargetActionsOrganism
AMuscarinic acetylcholine receptor M1
antagonist
Human
AMuscarinic acetylcholine receptor M2
antagonist
Human
AMuscarinic acetylcholine receptor M3
antagonist
Human
Absorption

The absolute oral bioavailability is 57.8% [5]. Tmax is 1-3 h after administration.

Volume of distribution

The estimated volume of distribution is 43.9 L [5].

Protein binding

Imidafenacin is 88% bounf by human plasma proteins [5]. It binds to serum albumin and α1-acid glycoprotein.

Metabolism

Thought to be metabolized v by CYP3A4 and UGT1A4 [5]. No active metabolites have been observed.

Route of elimination

10% is excreted in the urine as the parent compound [5]. Most is eliminated by metabolism thought to be mediated by CYP3A4 and UGT1A4.

Half life

The half life of elimination is 3 h [5].

Clearance

The estimated clearance is 21.2 L/h [5].

Toxicity

Clinically significant adverse reactions to imidafenacin are acute glaucoma (0.06%), urinary retention (0.03%), and heptic dysfunction (0.02%) [Label]. The most common adverse effects observed with imidafenacin are thirst (37.7%), constipation (13.6%).

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcetaminophenAcetaminophen may decrease the excretion rate of Imidafenacin which could result in a higher serum level.
Acetyl sulfisoxazoleThe metabolism of Imidafenacin can be decreased when combined with Acetyl sulfisoxazole.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Imidafenacin which could result in a higher serum level.
AgmatineThe risk or severity of adverse effects can be increased when Imidafenacin is combined with Agmatine.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Imidafenacin.
AlfuzosinThe metabolism of Imidafenacin can be decreased when combined with Alfuzosin.
AlprazolamAlprazolam may decrease the excretion rate of Imidafenacin which could result in a higher serum level.
AmcinonideThe metabolism of Amcinonide can be decreased when combined with Imidafenacin.
AmilorideAmiloride may increase the excretion rate of Imidafenacin which could result in a lower serum level and potentially a reduction in efficacy.
AmiodaroneThe metabolism of Imidafenacin can be decreased when combined with Amiodarone.
Food Interactions
Not Available

References

General References
  1. Kobayashi F, Yageta Y, Segawa M, Matsuzawa S: Effects of imidafenacin (KRP-197/ONO-8025), a new anti-cholinergic agent, on muscarinic acetylcholine receptors. High affinities for M3 and M1 receptor subtypes and selectivity for urinary bladder over salivary gland. Arzneimittelforschung. 2007;57(2):92-100. [PubMed:17396619]
  2. Miyachi H, Kiyota H, Uchiki H, Segawa M: Synthesis and antimuscarinic activity of a series of 4-(1-Imidazolyl)-2,2-diphenylbutyramides: discovery of potent and subtype-selective antimuscarinic agents. Bioorg Med Chem. 1999 Jun;7(6):1151-61. [PubMed:10428387]
  3. Kuraoka S, Ito Y, Wakuda H, Shinozuka K, Onoue S, Yamada S: Characterization of muscarinic receptor binding by the novel radioligand, [(3)H]imidafenacin, in the bladder and other tissues of rats. J Pharmacol Sci. 2016 Jul;131(3):184-9. doi: 10.1016/j.jphs.2016.06.002. Epub 2016 Jun 23. [PubMed:27430986]
  4. Chess-Williams R: Muscarinic receptors of the urinary bladder: detrusor, urothelial and prejunctional. Auton Autacoid Pharmacol. 2002 Jun;22(3):133-45. [PubMed:12452898]
  5. Ohno T, Nakade S, Nakayama K, Kitagawa J, Miyabe H, Konomi T, Miyata Y: Population pharmacokinetic analysis of a novel muscarinic receptor antagonist, imidafenacin, in healthy volunteers and overactive bladder patients. Drug Metab Pharmacokinet. 2008;23(6):456-63. [PubMed:19122340]
External Links
PubChem Compound
6433090
PubChem Substance
310265160
ChemSpider
4938278
ChEBI
134720
ChEMBL
CHEMBL53366
Wikipedia
Imidafenacin
FDA label
Download (294 KB)
MSDS
Download (77.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentUrinary Bladder, Overactive1
3CompletedTreatmentUrinary Bladder, Overactive2
4CompletedTreatmentUrinary Bladder, Overactive2
Not AvailableActive Not RecruitingNot AvailableUrinary Bladder, Overactive1
Not AvailableRecruitingNot AvailableUrinary Bladder, Overactive1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00951 mg/mLALOGPS
logP2.81ALOGPS
logP2.76ChemAxon
logS-4.5ALOGPS
pKa (Strongest Acidic)16.11ChemAxon
pKa (Strongest Basic)7.35ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area60.91 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity94.86 m3·mol-1ChemAxon
Polarizability35.03 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as diphenylmethanes. These 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
Phenylacetamides / N-substituted imidazoles / Fatty amides / Heteroaromatic compounds / Primary carboxylic acid amides / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives
show 1 more
Substituents
Diphenylmethane / Phenylacetamide / Fatty amide / N-substituted imidazole / Fatty acyl / Azole / Imidazole / Heteroaromatic compound / Primary carboxylic acid amide / Carboxamide group
show 12 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
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...
Gene Name
CHRM1
Uniprot ID
P11229
Uniprot Name
Muscarinic acetylcholine receptor M1
Molecular Weight
51420.375 Da
References
  1. Kuraoka S, Ito Y, Wakuda H, Shinozuka K, Onoue S, Yamada S: Characterization of muscarinic receptor binding by the novel radioligand, [(3)H]imidafenacin, in the bladder and other tissues of rats. J Pharmacol Sci. 2016 Jul;131(3):184-9. doi: 10.1016/j.jphs.2016.06.002. Epub 2016 Jun 23. [PubMed:27430986]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
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...
Gene Name
CHRM2
Uniprot ID
P08172
Uniprot Name
Muscarinic acetylcholine receptor M2
Molecular Weight
51714.605 Da
References
  1. Kuraoka S, Ito Y, Wakuda H, Shinozuka K, Onoue S, Yamada S: Characterization of muscarinic receptor binding by the novel radioligand, [(3)H]imidafenacin, in the bladder and other tissues of rats. J Pharmacol Sci. 2016 Jul;131(3):184-9. doi: 10.1016/j.jphs.2016.06.002. Epub 2016 Jun 23. [PubMed:27430986]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
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...
Gene Name
CHRM3
Uniprot ID
P20309
Uniprot Name
Muscarinic acetylcholine receptor M3
Molecular Weight
66127.445 Da
References
  1. Kuraoka S, Ito Y, Wakuda H, Shinozuka K, Onoue S, Yamada S: Characterization of muscarinic receptor binding by the novel radioligand, [(3)H]imidafenacin, in the bladder and other tissues of rats. J Pharmacol Sci. 2016 Jul;131(3):184-9. doi: 10.1016/j.jphs.2016.06.002. Epub 2016 Jun 23. [PubMed:27430986]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Ohno T, Nakade S, Nakayama K, Kitagawa J, Miyabe H, Konomi T, Miyata Y: Population pharmacokinetic analysis of a novel muscarinic receptor antagonist, imidafenacin, in healthy volunteers and overactive bladder patients. Drug Metab Pharmacokinet. 2008;23(6):456-63. [PubMed:19122340]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Protein homodimerization activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A4
Uniprot ID
P22310
Uniprot Name
UDP-glucuronosyltransferase 1-4
Molecular Weight
60024.535 Da
References
  1. Ohno T, Nakade S, Nakayama K, Kitagawa J, Miyabe H, Konomi T, Miyata Y: Population pharmacokinetic analysis of a novel muscarinic receptor antagonist, imidafenacin, in healthy volunteers and overactive bladder patients. Drug Metab Pharmacokinet. 2008;23(6):456-63. [PubMed:19122340]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Ohno T, Nakade S, Nakayama K, Kitagawa J, Miyabe H, Konomi T, Miyata Y: Population pharmacokinetic analysis of a novel muscarinic receptor antagonist, imidafenacin, in healthy volunteers and overactive bladder patients. Drug Metab Pharmacokinet. 2008;23(6):456-63. [PubMed:19122340]
Kind
Protein group
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...

Components:
References
  1. Ohno T, Nakade S, Nakayama K, Kitagawa J, Miyabe H, Konomi T, Miyata Y: Population pharmacokinetic analysis of a novel muscarinic receptor antagonist, imidafenacin, in healthy volunteers and overactive bladder patients. Drug Metab Pharmacokinet. 2008;23(6):456-63. [PubMed:19122340]

Drug created on October 26, 2015 11:45 / Updated on August 02, 2018 06:16