Identification

Name
Dapoxetine
Accession Number
DB04884
Type
Small Molecule
Groups
Investigational
Description

Dapoxetine is a selective serotonin reuptake inhibitor, for the treatment of premature ejaculation. In a phase II proof-of-concept study conducted by PPD, dapoxetine demonstrated a statistically significant increase in ejaculatory latency when compared to placebo. Alza submitted a NDA to the FDA for dapoxetine for the treatment of premature ejaculation in December 2004. In October 2005, the company received a FDA Non-Approvable letter from the FDA, at which time they planned to work with regulators to address outstanding questions.

Structure
Thumb
Synonyms
  • Dapoxetina
  • Dapoxetinum
External IDs
LY 210448 / LY-210448
Categories
UNII
GB2433A4M3
CAS number
119356-77-3
Weight
Average: 305.4134
Monoisotopic: 305.177964363
Chemical Formula
C21H23NO
InChI Key
USRHYDPUVLEVMC-FQEVSTJZSA-N
InChI
InChI=1S/C21H23NO/c1-22(2)20(18-10-4-3-5-11-18)15-16-23-21-14-8-12-17-9-6-7-13-19(17)21/h3-14,20H,15-16H2,1-2H3/t20-/m0/s1
IUPAC Name
dimethyl[(1S)-3-(naphthalen-1-yloxy)-1-phenylpropyl]amine
SMILES
CN(C)[C@@H](CCOC1=CC=CC2=CC=CC=C12)C1=CC=CC=C1

Pharmacology

Indication

For the treatment of premature ejaculation.

Pharmacodynamics

Dapoxetine is a selective serotonin reuptake inhibitor currently undergoing trials through Alza (under license from GenuPro, a collaboration between Eli Lilly and PPD). Dapoxetine is a short-acting SSRI drug currently being considered for approval by the Food and Drug Administration (FDA) for the treatment of premature ejaculation in men, which would make it the first drug approved for such treatment. Despite two clinical trials finished in 2006, experts doubt it will be approved by the FDA soon because SSRIs come with undesirable side-effects after long-term use, such as psychiatric problems, dermatological reactions, increase in body weight, lower sex-drive, nausea, headache, upset stomach and weakness, thus not significantly outweighing the benefit of premature ejaculation medication versus the risks. By contrast with SSRIs approved for depression, which take 2 weeks or longer to reach steady-state concentration, dapoxetine has a unique pharmacokinetic profile, with a short time to maximum serum concentration (about 1 h) and rapid elimination (initial half-life of 1-2 h).

Mechanism of action

The drug's mechanism of action is thought to be related to inhibition of neuronal reuptake of serotonin and subsequent potentiation of serotonin activity. The central ejaculatory neural circuit comprises spinal and cerebral areas that form a highly interconnected network. The sympathetic, parasympathetic, and somatic spinal centers, under the influence of sensory genital and cerebral stimuli integrated and processed at the spinal cord level, act in synergy to command physiologic events occurring during ejaculation. Experimental evidence indicates that serotonin (5-HT), throughout brain descending pathways, exerts an inhibitory role on ejaculation. To date, three 5-HT receptor subtypes (5-HT(1A), 5-HT(1B), and 5-HT(2C)) have been postulated to mediate 5-HT's modulating activity on ejaculation.

TargetActionsOrganism
U5-hydroxytryptamine receptor 1ANot AvailableHuman
U5-hydroxytryptamine receptor 1BNot AvailableHuman
U5-hydroxytryptamine receptor 2CNot AvailableHuman
Absorption

Rapidly absorbed.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

Initial half-life of 1-2 hours.

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

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of hemorrhage can be increased when Dapoxetine is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of hemorrhage can be increased when Dapoxetine is combined with (S)-Warfarin.
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic AcidDapoxetine may increase the orthostatic hypotensive activities of 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid.
2,4-thiazolidinedioneThe risk or severity of hypoglycemia can be increased when Dapoxetine is combined with 2,4-thiazolidinedione.
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of serotonin syndrome can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Dapoxetine.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when 2,5-Dimethoxy-4-ethylthioamphetamine is combined with Dapoxetine.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when 3,4-Methylenedioxyamphetamine is combined with Dapoxetine.
3,5-diiodothyropropionic acidThe therapeutic efficacy of 3,5-diiodothyropropionic acid can be decreased when used in combination with Dapoxetine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Dapoxetine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Dapoxetine.
Food Interactions
Not Available

References

General References
  1. Safarinejad MR: Safety and efficacy of dapoxetine in the treatment of premature ejaculation: a double-blind, placebo-controlled, fixed-dose, randomized study. Neuropsychopharmacology. 2008 May;33(6):1259-65. Epub 2007 Jul 11. [PubMed:17625501]
  2. Cirillo-Penn K, Modi NB: Dapoxetine and paroxetine for the treatment of premature ejaculation. Clin Neuropharmacol. 2007 Sep-Oct;30(5):315. [PubMed:17909314]
  3. McMahon C: Dapoxetine in the treatment of premature ejaculation. Clin Neuropharmacol. 2007 Sep-Oct;30(5):314-5. [PubMed:17909313]
  4. Wang WF, Chang L, Minhas S, Ralph DJ: Selective serotonin reuptake inhibitors in the treatment of premature ejaculation. Chin Med J (Engl). 2007 Jun 5;120(11):1000-6. [PubMed:17624269]
  5. Pryor JL, Althof SE, Steidle C, Rosen RC, Hellstrom WJ, Shabsigh R, Miloslavsky M, Kell S: Efficacy and tolerability of dapoxetine in treatment of premature ejaculation: an integrated analysis of two double-blind, randomised controlled trials. Lancet. 2006 Sep 9;368(9539):929-37. [PubMed:16962882]
  6. Hellstrom WJ, Heintz JW: Treatment of premature ejaculation: new drugs and treatment strategies. Curr Urol Rep. 2006 Nov;7(6):473-8. [PubMed:17052444]
  7. Modi NB, Dresser M, Desai D, Edgar C, Wesnes K: Dapoxetine has no pharmacokinetic or cognitive interactions with ethanol in healthy male volunteers. J Clin Pharmacol. 2007 Mar;47(3):315-22. [PubMed:17322143]
  8. Payne RE, Sadovsky R: Identifying and treating premature ejaculation: importance of the sexual history. Cleve Clin J Med. 2007 May;74 Suppl 3:S47-53. [PubMed:17546831]
External Links
KEGG Drug
D03649
PubChem Compound
71353
PubChem Substance
175426887
ChemSpider
64453
ChEBI
135962
ChEMBL
CHEMBL2110900
PharmGKB
PA166151992
Wikipedia
Dapoxetine
ATC Codes
G04BX14 — Dapoxetine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentDrug Interaction Potentiation2
1Unknown StatusTreatmentHealthy Male Subjects1
1, 2CompletedBasic SciencePremature Ejaculation1
3CompletedTreatmentEjaculation2
3CompletedTreatmentEjaculation / Erectile Dysfunction (ED) / Sexual Dysfunctions1
3CompletedTreatmentEjaculation / Sexual Dysfunctions1
3CompletedTreatmentErectile Dysfunction (ED)2
3CompletedTreatmentErectile Dysfunction (ED) / Sexual Dysfunctions1
3CompletedTreatmentSexual Dysfunction, Physiological1
Not AvailableNot Yet RecruitingNot AvailablePremature Ejaculation1
Not AvailableRecruitingBasic SciencePremature Ejaculation1

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 Solubility0.000837 mg/mLALOGPS
logP4.75ALOGPS
logP4.67ChemAxon
logS-5.6ALOGPS
pKa (Strongest Basic)9.04ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area12.47 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity96.14 m3·mol-1ChemAxon
Polarizability35 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9933
Blood Brain Barrier+0.9758
Caco-2 permeable+0.817
P-glycoprotein substrateSubstrate0.5085
P-glycoprotein inhibitor IInhibitor0.6464
P-glycoprotein inhibitor IINon-inhibitor0.8833
Renal organic cation transporterInhibitor0.74
CYP450 2C9 substrateNon-substrate0.7484
CYP450 2D6 substrateSubstrate0.7615
CYP450 3A4 substrateSubstrate0.7727
CYP450 1A2 substrateInhibitor0.9354
CYP450 2C9 inhibitorNon-inhibitor0.7353
CYP450 2D6 inhibitorNon-inhibitor0.5597
CYP450 2C19 inhibitorNon-inhibitor0.7689
CYP450 3A4 inhibitorNon-inhibitor0.8382
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6419
Ames testAMES toxic0.6626
CarcinogenicityNon-carcinogens0.8718
BiodegradationNot ready biodegradable0.9866
Rat acute toxicity2.5199 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6032
hERG inhibition (predictor II)Inhibitor0.663
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 naphthalenes. These are compounds containing a naphthalene moiety, which consists of two fused benzene rings.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Naphthalenes
Sub Class
Not Available
Direct Parent
Naphthalenes
Alternative Parents
Aralkylamines / Alkyl aryl ethers / Benzene and substituted derivatives / Trialkylamines / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Naphthalene / Aralkylamine / Alkyl aryl ether / Monocyclic benzene moiety / Tertiary aliphatic amine / Tertiary amine / Ether / Organic nitrogen compound / Organic oxygen compound / Organopnictogen compound
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive subst...
Gene Name
HTR1B
Uniprot ID
P28222
Uniprot Name
5-hydroxytryptamine receptor 1B
Molecular Weight
43567.535 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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, including ergot alkaloid derivatives, 1-2,5,-dimethoxy-4-...
Gene Name
HTR2C
Uniprot ID
P28335
Uniprot Name
5-hydroxytryptamine receptor 2C
Molecular Weight
51820.705 Da
References
  1. Wang WF, Chang L, Minhas S, Ralph DJ: Selective serotonin reuptake inhibitors in the treatment of premature ejaculation. Chin Med J (Engl). 2007 Jun 5;120(11):1000-6. [PubMed:17624269]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
Inhibitor
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. McMahon CG: Dapoxetine: a new option in the medical management of premature ejaculation. Ther Adv Urol. 2012 Oct;4(5):233-51. doi: 10.1177/1756287212453866. [PubMed:23024705]
  2. Gerotziafas GT, Mahe I, Elalamy I: New orally active anticoagulant agents for the prevention and treatment of venous thromboembolism in cancer patients. Ther Clin Risk Manag. 2014 Jun 13;10:423-36. doi: 10.2147/TCRM.S49063. eCollection 2014. [PubMed:24966680]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. McMahon CG: Dapoxetine: a new option in the medical management of premature ejaculation. Ther Adv Urol. 2012 Oct;4(5):233-51. doi: 10.1177/1756287212453866. [PubMed:23024705]

Drug created on October 21, 2007 05:51 / Updated on November 02, 2018 06:07