Identification

Name
Avanafil
Accession Number
DB06237
Type
Small Molecule
Groups
Approved
Description

Avanafil 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
  • Avanafilo
External IDs
TA-1790
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SpedraTablet100 mgOralMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet50 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
SpedraTablet50 mgOralMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet200 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
SpedraTablet50 mgOralMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
SpedraTablet200 mgOralMenarini International Operations Luxembourg S.A.2013-06-21Not applicableEu
International/Other Brands
Stendra
Categories
UNII
DR5S136IVO
CAS number
330784-47-9
Weight
Average: 483.951
Monoisotopic: 483.17856544
Chemical Formula
C23H26ClN7O3
InChI Key
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[C@H]2CO)C(=O)NCC2=NC=CC=N2)C=C1

Pharmacology

Indication

Treatment of erectile dysfunction in males.

Associated Conditions
Pharmacodynamics

Avanafil 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 action

Avanafil 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.

TargetActionsOrganism
AcGMP-specific 3',5'-cyclic phosphodiesterase
inhibitor
Human
Absorption

Avanafil 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 distribution
Not Available
Protein binding

99% 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 elimination

After 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 life

Mean elimination half-life = 5.36 - 10.66 hours

Clearance
Not Available
Toxicity

Avanafil is generally well tolerated. The most commonly reported adverse event are headache and facial flushing.

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

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Avanafil can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of Avanafil can be decreased when combined with (S)-Warfarin.
3,5-diiodothyropropionic acidThe metabolism of Avanafil can be decreased when combined with 3,5-diiodothyropropionic acid.
4-hydroxycoumarinThe metabolism of Avanafil can be decreased when combined with 4-hydroxycoumarin.
5-androstenedioneThe metabolism of Avanafil can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Avanafil can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of Avanafil can be decreased when combined with 6-O-benzylguanine.
AbemaciclibThe metabolism of Avanafil can be decreased when combined with Abemaciclib.
AbirateroneThe metabolism of Avanafil can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Avanafil can be decreased when combined with Acalabrutinib.
Food Interactions
  • When taken with a high-fat meal, time to maximum plasma concentration is prolonged- Tmax = 1 hour 20 minutes

References

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
KEGG Drug
D03217
PubChem Compound
9869929
PubChem Substance
175427065
ChemSpider
8045620
BindingDB
235766
ChEBI
66876
ChEMBL
CHEMBL1963681
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Avanafil
ATC Codes
G04BE10 — Avanafil
FDA label
Download (465 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceAvanfil ADME / Semen Exposure / Sperm Function1
1CompletedPreventionHealthy Volunteers1
1CompletedTreatmentErectile Dysfunction (ED)8
1CompletedTreatmentRenal1
2CompletedTreatmentErectile Dysfunction (ED)1
3CompletedTreatmentErectile Dysfunction (ED)5
3CompletedTreatmentSexual Function and Fertility Disorders NEC-Erectile Dysfunction1
4CompletedTreatmentErectile Dysfunction (ED)2
4CompletedTreatmentVision1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral100 mg
TabletOral200 mg
TabletOral50 mg
TabletOral100 mg/1
TabletOral200 mg/1
TabletOral50 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6656935No2003-12-022020-09-13Us
US7501409No2009-03-102023-05-05Us

Properties

State
Solid
Experimental Properties
Not 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 FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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)

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 pyrimidinecarboxamides. These are compounds containing a pyrimidine ring which bears a carboxamide.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazines
Sub Class
Pyrimidines and pyrimidine derivatives
Direct Parent
Pyrimidinecarboxamides
Alternative Parents
Anisoles / Benzylamines / Phenoxy compounds / Dialkylarylamines / Methoxybenzenes / Alkyl aryl ethers / Aminopyrimidines and derivatives / Secondary alkylarylamines / Chlorobenzenes / Aryl chlorides
show 12 more
Substituents
Pyrimidinecarboxamide / Anisole / Benzylamine / Phenol ether / Dialkylarylamine / Methoxybenzene / Phenoxy compound / Alkyl aryl ether / Aminopyrimidine / Chlorobenzene
show 30 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
monocarboxylic acid amide, organochlorine compound, pyrimidines, aromatic amide, prolinols (CHEBI:66876)

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, ...
Gene Name
PDE5A
Uniprot ID
O76074
Uniprot Name
cGMP-specific 3',5'-cyclic phosphodiesterase
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
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]

Drug created on March 19, 2008 10:18 / Updated on November 05, 2018 17:48