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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
SpedraTablet100 mgOral useMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet200 mgOral useMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet50 mgOral useMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet100 mgOral useMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet200 mgOral useMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet50 mgOral useMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet100 mgOral useMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet200 mgOral useMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet100 mgOral useMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet200 mgOral useMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet50 mgOral useMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
Stendratablet50 mg/1oralVIVUS, Inc.2013-12-27Not applicableUs
Stendratablet100 mg/1oralVIVUS, Inc.2013-12-27Not applicableUs
Stendratablet200 mg/1oralVIVUS, Inc.2013-12-27Not applicableUs
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 KeyInChIKey=WEAJZXNPAWBCOA-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
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
Pharmacology
IndicationTreatment of erectile dysfunction in males.
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.
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
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
TabletOral use100 mg
TabletOral use200 mg
TabletOral use50 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
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
Interactions
Drug Interactions
Drug
AmiodaroneThe serum concentration of Avanafil can be increased when it is combined with Amiodarone.
AprepitantThe serum concentration of Avanafil can be increased when it is combined with Aprepitant.
AtazanavirThe serum concentration of Avanafil can be increased when it is combined with Atazanavir.
AtomoxetineThe metabolism of Avanafil can be decreased when combined with Atomoxetine.
BexaroteneThe serum concentration of Avanafil can be decreased when it is combined with Bexarotene.
BoceprevirThe serum concentration of Avanafil can be increased when it is combined with Boceprevir.
BortezomibThe metabolism of Avanafil can be decreased when combined with Bortezomib.
BosentanThe serum concentration of Avanafil can be decreased when it is combined with Bosentan.
CarbamazepineThe metabolism of Avanafil can be increased when combined with Carbamazepine.
CeritinibThe serum concentration of Avanafil can be increased when it is combined with Ceritinib.
ClarithromycinThe serum concentration of Avanafil can be increased when it is combined with Clarithromycin.
ClemastineThe metabolism of Avanafil can be decreased when combined with Clemastine.
ClotrimazoleThe metabolism of Avanafil can be decreased when combined with Clotrimazole.
CobicistatThe serum concentration of Avanafil can be increased when it is combined with Cobicistat.
ConivaptanThe serum concentration of Avanafil can be increased when it is combined with Conivaptan.
CrizotinibThe metabolism of Avanafil can be decreased when combined with Crizotinib.
CyclosporineThe metabolism of Avanafil can be decreased when combined with Cyclosporine.
DabrafenibThe serum concentration of Avanafil can be decreased when it is combined with Dabrafenib.
DarunavirThe serum concentration of Avanafil can be increased when it is combined with Darunavir.
DasatinibThe serum concentration of Avanafil can be increased when it is combined with Dasatinib.
DeferasiroxThe serum concentration of Avanafil can be decreased when it is combined with Deferasirox.
DelavirdineThe metabolism of Avanafil can be decreased when combined with Delavirdine.
DexamethasoneThe serum concentration of Avanafil can be decreased when it is combined with Dexamethasone.
DihydroergotamineThe metabolism of Avanafil can be decreased when combined with Dihydroergotamine.
DiltiazemThe metabolism of Avanafil can be decreased when combined with Diltiazem.
DoxycyclineThe metabolism of Avanafil can be decreased when combined with Doxycycline.
DronedaroneThe metabolism of Avanafil can be decreased when combined with Dronedarone.
EfavirenzThe serum concentration of Avanafil can be decreased when it is combined with Efavirenz.
EnzalutamideThe serum concentration of Avanafil can be decreased when it is combined with Enzalutamide.
ErythromycinThe metabolism of Avanafil can be decreased when combined with Erythromycin.
Eslicarbazepine acetateThe serum concentration of Avanafil can be decreased when it is combined with Eslicarbazepine acetate.
EtravirineThe serum concentration of Avanafil can be decreased when it is combined with Etravirine.
FluconazoleThe metabolism of Avanafil can be decreased when combined with Fluconazole.
FluvoxamineThe metabolism of Avanafil can be decreased when combined with Fluvoxamine.
FosamprenavirThe metabolism of Avanafil can be decreased when combined with Fosamprenavir.
FosaprepitantThe serum concentration of Avanafil can be increased when it is combined with Fosaprepitant.
FosphenytoinThe metabolism of Avanafil can be increased when combined with Fosphenytoin.
Fusidic AcidThe serum concentration of Avanafil can be increased when it is combined with Fusidic Acid.
IdelalisibThe serum concentration of Avanafil can be increased when it is combined with Idelalisib.
ImatinibThe metabolism of Avanafil can be decreased when combined with Imatinib.
IndinavirThe serum concentration of Avanafil can be increased when it is combined with Indinavir.
IsavuconazoniumThe metabolism of Avanafil can be decreased when combined with Isavuconazonium.
IsradipineThe metabolism of Avanafil can be decreased when combined with Isradipine.
ItraconazoleThe serum concentration of Avanafil can be increased when it is combined with Itraconazole.
IvacaftorThe serum concentration of Avanafil can be increased when it is combined with Ivacaftor.
KetoconazoleThe serum concentration of Avanafil can be increased when it is combined with Ketoconazole.
LopinavirThe serum concentration of Avanafil can be increased when it is combined with Lopinavir.
LovastatinThe metabolism of Avanafil can be decreased when combined with Lovastatin.
LuliconazoleThe serum concentration of Avanafil can be increased when it is combined with Luliconazole.
MifepristoneThe metabolism of Avanafil can be decreased when combined with Mifepristone.
MitotaneThe serum concentration of Avanafil can be decreased when it is combined with Mitotane.
ModafinilThe serum concentration of Avanafil can be decreased when it is combined with Modafinil.
NafcillinThe serum concentration of Avanafil can be decreased when it is combined with Nafcillin.
NefazodoneThe serum concentration of Avanafil can be increased when it is combined with Nefazodone.
NelfinavirThe serum concentration of Avanafil can be increased when it is combined with Nelfinavir.
NetupitantThe serum concentration of Avanafil can be increased when it is combined with Netupitant.
NevirapineThe metabolism of Avanafil can be decreased when combined with Nevirapine.
NilotinibThe metabolism of Avanafil can be decreased when combined with Nilotinib.
OlaparibThe metabolism of Avanafil can be decreased when combined with Olaparib.
OsimertinibThe serum concentration of Avanafil can be increased when it is combined with Osimertinib.
PalbociclibThe serum concentration of Avanafil can be increased when it is combined with Palbociclib.
PentobarbitalThe metabolism of Avanafil can be increased when combined with Pentobarbital.
PhenobarbitalThe metabolism of Avanafil can be increased when combined with Phenobarbital.
PhenytoinThe metabolism of Avanafil can be increased when combined with Phenytoin.
PosaconazoleThe serum concentration of Avanafil can be increased when it is combined with Posaconazole.
PrimidoneThe metabolism of Avanafil can be increased when combined with Primidone.
RanolazineThe metabolism of Avanafil can be decreased when combined with Ranolazine.
RifabutinThe metabolism of Avanafil can be increased when combined with Rifabutin.
RifampicinThe metabolism of Avanafil can be increased when combined with Rifampicin.
RifapentineThe metabolism of Avanafil can be increased when combined with Rifapentine.
RitonavirThe serum concentration of Avanafil can be increased when it is combined with Ritonavir.
SaquinavirThe serum concentration of Avanafil can be increased when it is combined with Saquinavir.
SildenafilThe metabolism of Avanafil can be decreased when combined with Sildenafil.
SiltuximabThe serum concentration of Avanafil can be decreased when it is combined with Siltuximab.
SimeprevirThe serum concentration of Avanafil can be increased when it is combined with Simeprevir.
St. John's WortThe serum concentration of Avanafil can be decreased when it is combined with St. John's Wort.
StiripentolThe serum concentration of Avanafil can be increased when it is combined with Stiripentol.
SulfisoxazoleThe metabolism of Avanafil can be decreased when combined with Sulfisoxazole.
TelaprevirThe serum concentration of Avanafil can be increased when it is combined with Telaprevir.
TelithromycinThe serum concentration of Avanafil can be increased when it is combined with Telithromycin.
TiclopidineThe metabolism of Avanafil can be decreased when combined with Ticlopidine.
TocilizumabThe serum concentration of Avanafil can be decreased when it is combined with Tocilizumab.
VenlafaxineThe metabolism of Avanafil can be decreased when combined with Venlafaxine.
VerapamilThe metabolism of Avanafil can be decreased when combined with Verapamil.
VoriconazoleThe serum concentration of Avanafil can be increased when it is combined with Voriconazole.
ZiprasidoneThe metabolism of Avanafil can be decreased when combined with Ziprasidone.
Food Interactions
  • When taken with a high-fat meal, time to maximum plasma concentration is prolonged- Tmax = 1 hour 20 minutes

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 ]
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Drug created on March 19, 2008 10:18 / Updated on September 27, 2016 02:27