Identification

Name
Flibanserin
Accession Number
DB04908
Type
Small Molecule
Groups
Approved, Investigational
Description

Flibanserin is the first drug to be approved for hypoactive sexual desire disorder (HSDD) in premenopausal women by the FDA in August 2015. It was originally developed as an antidepressant medication by Boehringer Ingelheim, but showed lack of efficacy in trials and was further developed as a hypoactive sexual disorder drug by Sprout Pharmaceuticals. Flibanserin's mechanism of action is attributed to its high affinity for 5-HTA1 and 5-HTA2 receptors, displaying agonist activity on 5-HTA1 and antagonist on 5-HTA2, resulting in lowering of serotonin in the brain as well as an effect on increasing norepinephrine and dopamine neurotransmitters.

Structure
Thumb
Synonyms
  • BIMT-17
  • BIMT-17-BS
External IDs
BIMT 17 / BIMT 17 BS
Product Ingredients
IngredientUNIICASInChI Key
Flibanserin hydrochloride96XTC36K1B147359-76-0XGAGFLQFMFCIHZ-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AddyiTablet100 mgOralSprout Pharmaceuticals IncNot applicableNot applicableCanada
AddyiTablet, film coated100 mg/1OralSprout Pharmaceuticals, Inc.2015-08-18Not applicableUs
International/Other Brands
Ectris
Categories
UNII
37JK4STR6Z
CAS number
167933-07-5
Weight
Average: 390.4021
Monoisotopic: 390.166745929
Chemical Formula
C20H21F3N4O
InChI Key
PPRRDFIXUUSXRA-UHFFFAOYSA-N
InChI
InChI=1S/C20H21F3N4O/c21-20(22,23)15-4-3-5-16(14-15)26-11-8-25(9-12-26)10-13-27-18-7-2-1-6-17(18)24-19(27)28/h1-7,14H,8-13H2,(H,24,28)
IUPAC Name
1-(2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)-2,3-dihydro-1H-1,3-benzodiazol-2-one
SMILES
FC(F)(F)C1=CC(=CC=C1)N1CCN(CCN2C(=O)NC3=CC=CC=C23)CC1

Pharmacology

Indication

For the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women.

Associated Conditions
Pharmacodynamics
Not Available
Mechanism of action

Flibansetrin has high affinity for serotonin receptors in the brain: it acts as an agonist on 5-HT1A and an antagonist on 5-HT2A. In vivo, flibanserin binds equally to 5-HT1A and 5-HT2A receptors. However, under higher levels of brain 5-HT (i.e., under stress), flibanserin may occupy 5-HT2A receptors in higher proportion than 5-HT(1A) receptors. It may also moderately antagonize D4 (dopamine) receptors and 5-HT2B and 5-HTB2C. Its action on neurotransmitter receptors may contribute to reduction in serotonin levels and increase in dopamine and norepinephrine levels, all of which may play part in reward processing.

TargetActionsOrganism
A5-hydroxytryptamine receptor 1A
agonist
Human
A5-hydroxytryptamine receptor 2A
antagonist
Human
AD(4) dopamine receptor
antagonist
agonist
Human
Absorption

Flibanserin has an absolute oral availability of 33%.

Volume of distribution
Not Available
Protein binding

~98%, highly bound to proteins (mostly albumin) in serum.

Metabolism

Metabolism is primarily via CYP3A4, slightly CYP2C19. Minimal involvement of CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2D6. At least 35 metabolites of flibanserin are produced, 2 of which reach plasma concentrations as high as parent drug, however they are pharmacologically inactive.

Route of elimination

Elimination via feces (51%) and urine (44%) following a single oral 50 mg dose of flibanserin solution.

Half life

≈11 hours

Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Cytochrome P450 2C19CYP2C19*2ANot Available681G>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*2BNot Available681G>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*3Not Available636G>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*4Not Available1A>GEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*5Not Available1297C>TEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*6Not Available395G>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*7Not Available19294T>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*22Not Available557G>C / 991A>GEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*24Not Available99C>T / 991A>G  … show all Effect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*35Not Available12662A>GEffect InferredPoor drug metabolizer.Details

Interactions

Drug Interactions
DrugInteraction
7-NitroindazoleThe risk or severity of adverse effects can be increased when Flibanserin is combined with 7-Nitroindazole.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe metabolism of Flibanserin can be decreased when combined with 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline.
AcepromazineThe risk or severity of adverse effects can be increased when Flibanserin is combined with Acepromazine.
AceprometazineThe risk or severity of adverse effects can be increased when Flibanserin is combined with Aceprometazine.
Acetyl sulfisoxazoleThe risk or severity of adverse effects can be increased when Acetyl sulfisoxazole is combined with Flibanserin.
AdipiplonThe risk or severity of adverse effects can be increased when Flibanserin is combined with Adipiplon.
AgomelatineThe risk or severity of adverse effects can be increased when Flibanserin is combined with Agomelatine.
AlaproclateThe risk or severity of adverse effects can be increased when Flibanserin is combined with Alaproclate.
AlbendazoleThe metabolism of Flibanserin can be decreased when combined with Albendazole.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Flibanserin.
Food Interactions
Not Available

References

General References
  1. Invernizzi RW, Sacchetti G, Parini S, Acconcia S, Samanin R: Flibanserin, a potential antidepressant drug, lowers 5-HT and raises dopamine and noradrenaline in the rat prefrontal cortex dialysate: role of 5-HT(1A) receptors. Br J Pharmacol. 2003 Aug;139(7):1281-8. [PubMed:12890707]
  2. Scandroglio A, Monferini E, Borsini F: Ex vivo binding of flibanserin to serotonin 5-HT1A and 5-HT2A receptors. Pharmacol Res. 2001 Feb;43(2):179-83. [PubMed:11243720]
  3. Borsini F, Cesana R: Mechanism of action of flibanserin in the learned helplessness paradigm in rats. Eur J Pharmacol. 2001 Dec 14;433(1):81-9. [PubMed:11755137]
  4. Borsini F, Evans K, Jason K, Rohde F, Alexander B, Pollentier S: Pharmacology of flibanserin. CNS Drug Rev. 2002 Summer;8(2):117-42. [PubMed:12177684]
  5. Deeks ED: Flibanserin: First Global Approval. Drugs. 2015 Oct;75(15):1815-22. doi: 10.1007/s40265-015-0474-y. [PubMed:26412054]
  6. Stahl SM: Mechanism of action of flibanserin, a multifunctional serotonin agonist and antagonist (MSAA), in hypoactive sexual desire disorder. CNS Spectr. 2015 Feb;20(1):1-6. doi: 10.1017/S1092852914000832. Epub 2015 Feb 9. [PubMed:25659981]
External Links
KEGG Drug
D02577
PubChem Compound
6918248
PubChem Substance
175426897
ChemSpider
5293454
ChEBI
90865
ChEMBL
CHEMBL231068
PharmGKB
PA166153431
Drugs.com
Drugs.com Drug Page
Wikipedia
Flibanserin
ATC Codes
G02CX02 — Flibanserin
AHFS Codes
  • 28:92.00 — Miscellaneous Central Nervous System Agents
FDA label
Download (788 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentSexual Dysfunctions, Psychological1
3CompletedTreatmentSexual Dysfunctions, Psychological7
3TerminatedTreatmentSexual Dysfunctions, Psychological3
4Active Not RecruitingTreatmentHypoactive Sexual Desire Disorder (HSDD)1
Not AvailableRecruitingBasic ScienceHypoactive Sexual Desire Disorder (HSDD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral100 mg
Tablet, film coatedOral100 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7151103No2003-05-092023-05-09Us
US8227471No2003-05-092023-05-09Us
US7420057No2002-08-012022-08-01Us
US9468639No2002-10-162022-10-16Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.178 mg/mLALOGPS
logP3.32ALOGPS
logP3.83ChemAxon
logS-3.3ALOGPS
pKa (Strongest Acidic)12.91ChemAxon
pKa (Strongest Basic)7.03ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area38.82 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity103.65 m3·mol-1ChemAxon
Polarizability38.69 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9857
Caco-2 permeable-0.7652
P-glycoprotein substrateSubstrate0.6865
P-glycoprotein inhibitor IInhibitor0.8895
P-glycoprotein inhibitor IIInhibitor0.8741
Renal organic cation transporterInhibitor0.6378
CYP450 2C9 substrateNon-substrate0.7906
CYP450 2D6 substrateNon-substrate0.5905
CYP450 3A4 substrateSubstrate0.6954
CYP450 1A2 substrateInhibitor0.8379
CYP450 2C9 inhibitorNon-inhibitor0.7028
CYP450 2D6 inhibitorInhibitor0.5876
CYP450 2C19 inhibitorNon-inhibitor0.59
CYP450 3A4 inhibitorInhibitor0.7523
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.9005
Ames testNon AMES toxic0.6798
CarcinogenicityNon-carcinogens0.9354
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6546 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6138
hERG inhibition (predictor II)Inhibitor0.9486
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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 phenylpiperazines. These are compounds containing a phenylpiperazine skeleton, which consists of a piperazine bound to a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazinanes
Sub Class
Piperazines
Direct Parent
Phenylpiperazines
Alternative Parents
N-arylpiperazines / Trifluoromethylbenzenes / Benzimidazoles / Aniline and substituted anilines / Dialkylarylamines / N-alkylpiperazines / N-substituted imidazoles / Heteroaromatic compounds / Trialkylamines / Ureas
show 7 more
Substituents
Phenylpiperazine / N-arylpiperazine / Trifluoromethylbenzene / Benzimidazole / Tertiary aliphatic/aromatic amine / Aniline or substituted anilines / Dialkylarylamine / N-alkylpiperazine / Monocyclic benzene moiety / N-substituted imidazole
show 21 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers...
Gene Name
HTR1A
Uniprot ID
P08908
Uniprot Name
5-hydroxytryptamine receptor 1A
Molecular Weight
46106.335 Da
References
  1. Invernizzi RW, Sacchetti G, Parini S, Acconcia S, Samanin R: Flibanserin, a potential antidepressant drug, lowers 5-HT and raises dopamine and noradrenaline in the rat prefrontal cortex dialysate: role of 5-HT(1A) receptors. Br J Pharmacol. 2003 Aug;139(7):1281-8. [PubMed:12890707]
  2. Borsini F, Evans K, Jason K, Rohde F, Alexander B, Pollentier S: Pharmacology of flibanserin. CNS Drug Rev. 2002 Summer;8(2):117-42. [PubMed:12177684]
  3. Deeks ED: Flibanserin: First Global Approval. Drugs. 2015 Oct;75(15):1815-22. doi: 10.1007/s40265-015-0474-y. [PubMed:26412054]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Virus receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodop...
Gene Name
HTR2A
Uniprot ID
P28223
Uniprot Name
5-hydroxytryptamine receptor 2A
Molecular Weight
52602.58 Da
References
  1. Borsini F, Evans K, Jason K, Rohde F, Alexander B, Pollentier S: Pharmacology of flibanserin. CNS Drug Rev. 2002 Summer;8(2):117-42. [PubMed:12177684]
  2. Invernizzi RW, Sacchetti G, Parini S, Acconcia S, Samanin R: Flibanserin, a potential antidepressant drug, lowers 5-HT and raises dopamine and noradrenaline in the rat prefrontal cortex dialysate: role of 5-HT(1A) receptors. Br J Pharmacol. 2003 Aug;139(7):1281-8. [PubMed:12890707]
  3. Deeks ED: Flibanserin: First Global Approval. Drugs. 2015 Oct;75(15):1815-22. doi: 10.1007/s40265-015-0474-y. [PubMed:26412054]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
Agonist
General Function
Sh3 domain binding
Specific Function
Dopamine receptor responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior. Its activity is mediated by G proteins ...
Gene Name
DRD4
Uniprot ID
P21917
Uniprot Name
D(4) dopamine receptor
Molecular Weight
48359.86 Da
References
  1. Borsini F, Evans K, Jason K, Rohde F, Alexander B, Pollentier S: Pharmacology of flibanserin. CNS Drug Rev. 2002 Summer;8(2):117-42. [PubMed:12177684]
  2. Invernizzi RW, Sacchetti G, Parini S, Acconcia S, Samanin R: Flibanserin, a potential antidepressant drug, lowers 5-HT and raises dopamine and noradrenaline in the rat prefrontal cortex dialysate: role of 5-HT(1A) receptors. Br J Pharmacol. 2003 Aug;139(7):1281-8. [PubMed:12890707]
  3. Deeks ED: Flibanserin: First Global Approval. Drugs. 2015 Oct;75(15):1815-22. doi: 10.1007/s40265-015-0474-y. [PubMed:26412054]

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. Deeks ED: Flibanserin: First Global Approval. Drugs. 2015 Oct;75(15):1815-22. doi: 10.1007/s40265-015-0474-y. [PubMed:26412054]

Drug created on October 21, 2007 16:23 / Updated on September 23, 2018 19:37