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Identification
NameAvanafil
Accession NumberDB06237
TypeSmall Molecule
GroupsApproved
DescriptionAvanafil is a new phosphodiesterase-5 inhibitor that is faster acting and more selective than other drugs belonging to the same class. Chemically, it is a derivative of pyrimidine and is only available as the S-enantiomer. FDA approved on April 27, 2012.
Structure
Thumb
Synonyms
(S)-4-(3-Chloro-4-methoxybenzylamino)-2-(2-hydroxymethylpyrrolidin-1-yl)-N-pyrimidin-2-ylmethyl-5-pyrimidinecarboxamide
Stendra
TA-1790
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SpedraTablet200 mgOralMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet50 mgOralMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet100 mgOralMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet200 mgOralMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet50 mgOralMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet100 mgOralMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet200 mgOralMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet50 mgOralMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet100 mgOralMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet200 mgOralMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet100 mgOralMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
StendraTablet50 mg/1OralVIVUS, Inc.2013-12-272018-11-30Us
StendraTablet100 mg/1OralVIVUS, Inc.2013-12-272018-11-30Us
StendraTablet200 mg/1OralVIVUS, Inc.2013-12-272018-11-30Us
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIDR5S136IVO
CAS number330784-47-9
WeightAverage: 483.951
Monoisotopic: 483.17856544
Chemical FormulaC23H26ClN7O3
InChI KeyWEAJZXNPAWBCOA-INIZCTEOSA-N
InChI
InChI=1S/C23H26ClN7O3/c1-34-19-6-5-15(10-18(19)24)11-27-21-17(22(33)28-13-20-25-7-3-8-26-20)12-29-23(30-21)31-9-2-4-16(31)14-32/h3,5-8,10,12,16,32H,2,4,9,11,13-14H2,1H3,(H,28,33)(H,27,29,30)/t16-/m0/s1
IUPAC Name
4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide
SMILES
COC1=C(Cl)C=C(CNC2=C(C=NC(=N2)N2CCC[[email protected]]2CO)C(=O)NCC2=NC=CC=N2)C=C1
Pharmacology
IndicationTreatment of erectile dysfunction in males.
Structured Indications
PharmacodynamicsAvanafil is a strong, competitive inhibitor of PDE5. It is also 100-times more potent for PDE5 than PDE6. The IC50 of avanafil is 5.2 nM. Compared to other PDE5 inhibitor like sildenafil and vardenafil, it is 16- and 21-fold more selective for PDE5 respectively. Avanafil does not bind to PDE6 and PDE11 to a considerable degree. The impact of this finding is that avanafil is less likely to cause side effects such as visual disturbances and myalgia. These are side effects that patients on sildenafil or tadalafil are more likely to experience. Furthermore, single oral doses of avanafil (200 mg) administered to healthy male volunteers resulted in mean changes from baseline in systolic/diastolic blood pressure of -5.3/-3.7 mmHg at 1 hour after dosing. Avanafil does not causes changes in QTc interval or ventricular repolarization.
Mechanism of actionAvanafil is a selective phosphodiesterase 5 (PDE5) enzyme inhibitor used for the treatment of erectile dysfunction caused by diabetes, age induced oxidative stress or other complications. Avanafil inhibits the cGMP specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum located around the penis. Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) by avanafil enhances erectile function by increasing the amount of cGMP.
TargetKindPharmacological actionActionsOrganismUniProt ID
cGMP-specific 3',5'-cyclic phosphodiesteraseProteinyes
inhibitor
HumanO76074 details
Related Articles
AbsorptionAvanafil is rapidly absorbed and does not accumulate following multiple doses. Tmax = 30 - 45 minutes; Time to peak response = 10 minutes (20 minutes shorter than sildenafil)
Volume of distributionNot Available
Protein binding99% bound to plasma protein. Protein binding is independent of total drug concentrations, age, renal and hepatic function.
Metabolism

Avanafil is hepatically metabolized primarily by the enzyme, CYP3A4. Two major metabolites are formed, M4 and M16. M4 has 4% of the pharmacologic activity of avanafil. M16 is an inactive metabolite.

Route of eliminationAfter oral administration, avanafil is excreted as metabolites predominantly in the feces (approximately 62% of administered oral dose) and to a lesser extent in the urine (approximately 21% of the administered oral dose).
Half lifeMean elimination half-life = 5.36 - 10.66 hours
ClearanceNot Available
ToxicityAvanafil is generally well tolerated. The most commonly reported adverse event are headache and facial flushing.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
Interactions
Drug Interactions
DrugInteractionDrug group
AmiodaroneThe serum concentration of Avanafil can be increased when it is combined with Amiodarone.Approved, Investigational
AprepitantThe serum concentration of Avanafil can be increased when it is combined with Aprepitant.Approved, Investigational
AtazanavirThe serum concentration of Avanafil can be increased when it is combined with Atazanavir.Approved, Investigational
AtomoxetineThe serum concentration of Avanafil can be increased when it is combined with Atomoxetine.Approved
BexaroteneThe serum concentration of Avanafil can be decreased when it is combined with Bexarotene.Approved, Investigational
BoceprevirThe serum concentration of Avanafil can be increased when it is combined with Boceprevir.Approved
BortezomibThe serum concentration of Avanafil can be increased when it is combined with Bortezomib.Approved, Investigational
BosentanThe serum concentration of Avanafil can be decreased when it is combined with Bosentan.Approved, Investigational
CarbamazepineThe metabolism of Avanafil can be increased when combined with Carbamazepine.Approved, Investigational
CeritinibThe serum concentration of Avanafil can be increased when it is combined with Ceritinib.Approved
ClarithromycinThe serum concentration of Avanafil can be increased when it is combined with Clarithromycin.Approved
ClemastineThe serum concentration of Avanafil can be increased when it is combined with Clemastine.Approved
ClotrimazoleThe serum concentration of Avanafil can be increased when it is combined with Clotrimazole.Approved, Vet Approved
CobicistatThe serum concentration of Avanafil can be increased when it is combined with Cobicistat.Approved
ConivaptanThe serum concentration of Avanafil can be increased when it is combined with Conivaptan.Approved, Investigational
CrizotinibThe serum concentration of Avanafil can be increased when it is combined with Crizotinib.Approved
CyclosporineThe serum concentration of Avanafil can be increased when it is combined with Cyclosporine.Approved, Investigational, Vet Approved
DabrafenibThe serum concentration of Avanafil can be decreased when it is combined with Dabrafenib.Approved
DarunavirThe serum concentration of Avanafil can be increased when it is combined with Darunavir.Approved
DasatinibThe serum concentration of Avanafil can be increased when it is combined with Dasatinib.Approved, Investigational
DeferasiroxThe serum concentration of Avanafil can be decreased when it is combined with Deferasirox.Approved, Investigational
DelavirdineThe serum concentration of Avanafil can be increased when it is combined with Delavirdine.Approved
DexamethasoneThe serum concentration of Avanafil can be decreased when it is combined with Dexamethasone.Approved, Investigational, Vet Approved
DihydroergotamineThe serum concentration of Avanafil can be increased when it is combined with Dihydroergotamine.Approved
DiltiazemThe serum concentration of Avanafil can be increased when it is combined with Diltiazem.Approved
DoxycyclineThe serum concentration of Avanafil can be increased when it is combined with Doxycycline.Approved, Investigational, Vet Approved
DronedaroneThe serum concentration of Avanafil can be increased when it is combined with Dronedarone.Approved
EfavirenzThe serum concentration of Avanafil can be decreased when it is combined with Efavirenz.Approved, Investigational
EnzalutamideThe serum concentration of Avanafil can be decreased when it is combined with Enzalutamide.Approved
ErythromycinThe serum concentration of Avanafil can be increased when it is combined with Erythromycin.Approved, Vet Approved
Eslicarbazepine acetateThe serum concentration of Avanafil can be decreased when it is combined with Eslicarbazepine acetate.Approved
EtravirineThe serum concentration of Avanafil can be decreased when it is combined with Etravirine.Approved
FluconazoleThe serum concentration of Avanafil can be increased when it is combined with Fluconazole.Approved
FluvoxamineThe serum concentration of Avanafil can be increased when it is combined with Fluvoxamine.Approved, Investigational
FosamprenavirThe serum concentration of Avanafil can be increased when it is combined with Fosamprenavir.Approved
FosaprepitantThe serum concentration of Avanafil can be increased when it is combined with Fosaprepitant.Approved
FosphenytoinThe metabolism of Avanafil can be increased when combined with Fosphenytoin.Approved
Fusidic AcidThe serum concentration of Avanafil can be increased when it is combined with Fusidic Acid.Approved
IdelalisibThe serum concentration of Avanafil can be increased when it is combined with Idelalisib.Approved
ImatinibThe serum concentration of Avanafil can be increased when it is combined with Imatinib.Approved
IndinavirThe serum concentration of Avanafil can be increased when it is combined with Indinavir.Approved
IsavuconazoniumThe serum concentration of Avanafil can be increased when it is combined with Isavuconazonium.Approved, Investigational
IsradipineThe serum concentration of Avanafil can be increased when it is combined with Isradipine.Approved
ItraconazoleThe serum concentration of Avanafil can be increased when it is combined with Itraconazole.Approved, Investigational
IvacaftorThe serum concentration of Avanafil can be increased when it is combined with Ivacaftor.Approved
KetoconazoleThe serum concentration of Avanafil can be increased when it is combined with Ketoconazole.Approved, Investigational
LopinavirThe serum concentration of Avanafil can be increased when it is combined with Lopinavir.Approved
LovastatinThe serum concentration of Avanafil can be increased when it is combined with Lovastatin.Approved, Investigational
LuliconazoleThe serum concentration of Avanafil can be increased when it is combined with Luliconazole.Approved
LumacaftorThe metabolism of Avanafil can be increased when combined with Lumacaftor.Approved
MifepristoneThe serum concentration of Avanafil can be increased when it is combined with Mifepristone.Approved, Investigational
MitotaneThe serum concentration of Avanafil can be decreased when it is combined with Mitotane.Approved
ModafinilThe serum concentration of Avanafil can be decreased when it is combined with Modafinil.Approved, Investigational
NafcillinThe serum concentration of Avanafil can be decreased when it is combined with Nafcillin.Approved
NefazodoneThe serum concentration of Avanafil can be increased when it is combined with Nefazodone.Approved, Withdrawn
NelfinavirThe serum concentration of Avanafil can be increased when it is combined with Nelfinavir.Approved
NetupitantThe serum concentration of Avanafil can be increased when it is combined with Netupitant.Approved
NevirapineThe serum concentration of Avanafil can be increased when it is combined with Nevirapine.Approved
NilotinibThe serum concentration of Avanafil can be increased when it is combined with Nilotinib.Approved, Investigational
OlaparibThe serum concentration of Avanafil can be increased when it is combined with Olaparib.Approved
OsimertinibThe serum concentration of Avanafil can be increased when it is combined with Osimertinib.Approved
PalbociclibThe serum concentration of Avanafil can be increased when it is combined with Palbociclib.Approved
PentobarbitalThe metabolism of Avanafil can be increased when combined with Pentobarbital.Approved, Vet Approved
PhenobarbitalThe metabolism of Avanafil can be increased when combined with Phenobarbital.Approved
PhenytoinThe metabolism of Avanafil can be increased when combined with Phenytoin.Approved, Vet Approved
PosaconazoleThe serum concentration of Avanafil can be increased when it is combined with Posaconazole.Approved, Investigational, Vet Approved
PrimidoneThe metabolism of Avanafil can be increased when combined with Primidone.Approved, Vet Approved
RanolazineThe serum concentration of Avanafil can be increased when it is combined with Ranolazine.Approved, Investigational
RifabutinThe metabolism of Avanafil can be increased when combined with Rifabutin.Approved
RifampicinThe metabolism of Avanafil can be increased when combined with Rifampicin.Approved
RifapentineThe metabolism of Avanafil can be increased when combined with Rifapentine.Approved
RitonavirThe serum concentration of Avanafil can be increased when it is combined with Ritonavir.Approved, Investigational
SaquinavirThe serum concentration of Avanafil can be increased when it is combined with Saquinavir.Approved, Investigational
SildenafilThe serum concentration of Avanafil can be increased when it is combined with Sildenafil.Approved, Investigational
SiltuximabThe serum concentration of Avanafil can be decreased when it is combined with Siltuximab.Approved
SimeprevirThe serum concentration of Avanafil can be increased when it is combined with Simeprevir.Approved
St. John's WortThe serum concentration of Avanafil can be decreased when it is combined with St. John's Wort.Nutraceutical
StiripentolThe serum concentration of Avanafil can be increased when it is combined with Stiripentol.Approved
SulfisoxazoleThe serum concentration of Avanafil can be increased when it is combined with Sulfisoxazole.Approved, Vet Approved
TelaprevirThe serum concentration of Avanafil can be increased when it is combined with Telaprevir.Approved
TelithromycinThe serum concentration of Avanafil can be increased when it is combined with Telithromycin.Approved
TiclopidineThe serum concentration of Avanafil can be increased when it is combined with Ticlopidine.Approved
TocilizumabThe serum concentration of Avanafil can be decreased when it is combined with Tocilizumab.Approved
VenlafaxineThe serum concentration of Avanafil can be increased when it is combined with Venlafaxine.Approved
VerapamilThe serum concentration of Avanafil can be increased when it is combined with Verapamil.Approved
VoriconazoleThe serum concentration of Avanafil can be increased when it is combined with Voriconazole.Approved, Investigational
ZiprasidoneThe serum concentration of Avanafil can be increased when it is combined with Ziprasidone.Approved
Food Interactions
  • When taken with a high-fat meal, time to maximum plasma concentration is prolonged- Tmax = 1 hour 20 minutes
References
Synthesis ReferenceNot Available
General References
  1. Gur S, Sikka SC, Hellstrom WJ: Novel phosphodiesterase-5 (PDE5) inhibitors in the alleviation of erectile dysfunction due to diabetes and ageing-induced oxidative stress. Expert Opin Investig Drugs. 2008 Jun;17(6):855-64. doi: 10.1517/13543784.17.6.855 . [PubMed:18491987 ]
  2. Bruzziches R, Francomano D, Gareri P, Lenzi A, Aversa A: An update on pharmacological treatment of erectile dysfunction with phosphodiesterase type 5 inhibitors. Expert Opin Pharmacother. 2013 Jul;14(10):1333-44. doi: 10.1517/14656566.2013.799665. Epub 2013 May 16. [PubMed:23675780 ]
  3. Kedia GT, Uckert S, Assadi-Pour F, Kuczyk MA, Albrecht K: Avanafil for the treatment of erectile dysfunction: initial data and clinical key properties. Ther Adv Urol. 2013 Feb;5(1):35-41. doi: 10.1177/1756287212466282. [PubMed:23372609 ]
External Links
ATC CodesG04BE10
AHFS Codes
  • 24:12.12
PDB EntriesNot Available
FDA labelDownload (465 KB)
MSDSNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9958
Blood Brain Barrier-0.7165
Caco-2 permeable-0.61
P-glycoprotein substrateSubstrate0.672
P-glycoprotein inhibitor INon-inhibitor0.6724
P-glycoprotein inhibitor IIInhibitor0.9038
Renal organic cation transporterNon-inhibitor0.5282
CYP450 2C9 substrateNon-substrate0.7215
CYP450 2D6 substrateNon-substrate0.795
CYP450 3A4 substrateSubstrate0.6184
CYP450 1A2 substrateNon-inhibitor0.5
CYP450 2C9 inhibitorNon-inhibitor0.5841
CYP450 2D6 inhibitorNon-inhibitor0.7495
CYP450 2C19 inhibitorNon-inhibitor0.5892
CYP450 3A4 inhibitorNon-inhibitor0.549
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5277
Ames testNon AMES toxic0.6096
CarcinogenicityNon-carcinogens0.8809
BiodegradationNot ready biodegradable0.9929
Rat acute toxicity2.5077 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6671
hERG inhibition (predictor II)Inhibitor0.8671
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
TabletOral100 mg
TabletOral200 mg
TabletOral50 mg
TabletOral100 mg/1
TabletOral200 mg/1
TabletOral50 mg/1
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6656935 No2000-09-132020-09-13Us
US7501409 No2003-05-052023-05-05Us
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0297 mg/mLALOGPS
logP2.42ALOGPS
logP2.78ChemAxon
logS-4.2ALOGPS
pKa (Strongest Acidic)12.53ChemAxon
pKa (Strongest Basic)5.54ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area125.39 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity131.75 m3·mol-1ChemAxon
Polarizability50.87 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as pyrimidinecarboxamides. These are compounds containing a pyrimidine ring which bears a carboxamide.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassDiazines
Sub ClassPyrimidines and pyrimidine derivatives
Direct ParentPyrimidinecarboxamides
Alternative Parents
Substituents
  • Pyrimidinecarboxamide
  • Methoxybenzene
  • Dialkylarylamine
  • Phenylmethylamine
  • Phenol ether
  • Benzylamine
  • Anisole
  • Secondary aliphatic/aromatic amine
  • Halobenzene
  • Chlorobenzene
  • Aminopyrimidine
  • Alkyl aryl ether
  • Imidolactam
  • Benzenoid
  • Monocyclic benzene moiety
  • Aryl halide
  • Aryl chloride
  • Heteroaromatic compound
  • Vinylogous amide
  • Pyrrolidine
  • Tertiary amine
  • Secondary carboxylic acid amide
  • Carboxamide group
  • Azacycle
  • Secondary amine
  • Ether
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Primary alcohol
  • Organooxygen compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Carbonyl group
  • Amine
  • Alcohol
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Metal ion binding
Specific Function:
Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP (PubMed:9714779, PubMed:15489334). Specifically regulates nitric-oxide-generated cGMP (PubMed:15489334).
Gene Name:
PDE5A
Uniprot ID:
O76074
Molecular Weight:
99984.14 Da
References
  1. Kedia GT, Uckert S, Assadi-Pour F, Kuczyk MA, Albrecht K: Avanafil for the treatment of erectile dysfunction: initial data and clinical key properties. Ther Adv Urol. 2013 Feb;5(1):35-41. doi: 10.1177/1756287212466282. [PubMed:23372609 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Bruzziches R, Francomano D, Gareri P, Lenzi A, Aversa A: An update on pharmacological treatment of erectile dysfunction with phosphodiesterase type 5 inhibitors. Expert Opin Pharmacother. 2013 Jul;14(10):1333-44. doi: 10.1517/14656566.2013.799665. Epub 2013 May 16. [PubMed:23675780 ]
Comments
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Drug created on March 19, 2008 10:18 / Updated on December 08, 2016 02:40