Avanafil

Synonyms :
(S)-4-(3-Chloro-4-methoxybenzylamino)-2-(2-hydroxymethylpyrrolidin-1-yl)-N-pyrimidin-2-ylmethyl-5-pyrimidinecarboxamide, Stendra, TA-1790

Status : approved

Therapeutic Classification

UROLOGICALS

GENITO URINARY SYSTEM AND SEX HORMONES
UROLOGICALS
UROLOGICALS

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.

Used

Treatment of erectile dysfunction in males.

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.

Dosage

Form Route Strength
Tablet oral 100 mg
Tablet oral 200 mg
Tablet oral 50 mg

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.

Toxic Effect

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

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.

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)

Half Life

Mean elimination half-life = 5.36 – 10.66 hours

Protein Binding

99% bound to plasma protein. Protein binding is independent of total drug concentrations, age, renal and hepatic function.

Elimination Route

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).

Chemical Classification

This compound belongs to the class of organic compounds known as pyrimidinecarboxamides. These are compounds containing a pyrimidine ring which bears a carboxamide.

Pyrimidinecarboxamides

Organic compounds

Organoheterocyclic compounds

Diazines

Pyrimidines and pyrimidine derivatives

Chemical Name

(S)-4-(3-Chloro-4-methoxybenzylamino)-2-(2-hydroxymethylpyrrolidin-1-yl)-N-pyrimidin-2-ylmethyl-5-pyrimidinecarboxamide

Brands

name Dosage form Country
Stendra tablet US
Stendra tablet US
Stendra tablet US

Drug Drug Interactions

  •  Alprostadil  : Phosphodiesterase 5 Inhibitors may enhance the adverse/toxic effect of Alprostadil.
  •  Amyl Nitrite  : Phosphodiesterase 5 Inhibitors may enhance the vasodilatory effect of Amyl Nitrite.
  •  Aprepitant  : CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil.
  •  Atazanavir  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil.
  •  Boceprevir  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil.
  •  Bosentan  : May decrease the serum concentration of Phosphodiesterase 5 Inhibitors. Phosphodiesterase 5 Inhibitors may increase the serum concentration of Bosentan.
  •  Bosentan  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Ceritinib  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil.
  •  Clarithromycin  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil.
  •  Cobicistat  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil.
  •  Conivaptan  : May increase the serum concentration of CYP3A4 Substrates.
  •  Crizotinib  : CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil.
  •  Dabrafenib  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Dapoxetine  : May enhance the orthostatic hypotensive effect of Phosphodiesterase 5 Inhibitors.
  •  Darunavir  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil.
  •  Dasatinib  : May increase the serum concentration of CYP3A4 Substrates.
  •  Deferasirox  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Delavirdine  : CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil.
  •  Diltiazem  : CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil.
  •  Dronedarone  : CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil.
  •  Erythromycin  : CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil.
  •  Etravirine  : May decrease the serum concentration of Phosphodiesterase 5 Inhibitors.
  •  Fluconazole  : May increase the serum concentration of Avanafil.
  •  Fosamprenavir  : CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil.
  •  Fosaprepitant  : May increase the serum concentration of CYP3A4 Substrates.
  •  Idelalisib  : May increase the serum concentration of CYP3A4 Substrates.
  •  Imatinib  : CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil.
  •  Indinavir  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil.
  •  Isavuconazonium  : CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil.
  •  Itraconazole  : May increase the serum concentration of Avanafil.
  •  Ivacaftor  : May increase the serum concentration of CYP3A4 Substrates.
  •  Ketoconazole  : Ketoconazole (Systemic) may increase the serum concentration of Avanafil.
  •  Lopinavir  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil.
  •  Lorcaserin  : May enhance the adverse/toxic effect of Phosphodiesterase 5 Inhibitors. Specifically, the risk of developing priapism may be increased.
  •  Luliconazole  : May increase the serum concentration of CYP3A4 Substrates.
  •  Mifepristone  : May increase the serum concentration of CYP3A4 Substrates.
  •  Mitotane  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Nefazodone  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil.
  •  Nelfinavir  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil.
  •  Netupitant  : CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil.
  •  Nilotinib  : CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil.
  •  Palbociclib  : May increase the serum concentration of CYP3A4 Substrates.
  •  Posaconazole  : May increase the serum concentration of Avanafil.
  •  Riociguat  : Phosphodiesterase 5 Inhibitors may enhance the hypotensive effect of Riociguat.
  •  Ritonavir  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil.
  •  Saquinavir  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil.
  •  Siltuximab  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Simeprevir  : May increase the serum concentration of CYP3A4 Substrates.
  •  Simeprevir  : May increase the serum concentration of Phosphodiesterase 5 Inhibitors.
  •  Stiripentol  : May increase the serum concentration of CYP3A4 Substrates.
  •  Sulfisoxazole  : CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil.
  •  Tadalafil  : May enhance the adverse/toxic effect of other Phosphodiesterase 5 Inhibitors.
  •  Telaprevir  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil.
  •  Telithromycin  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil.
  •  Tetrahydrobiopterin  : May enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors.
  •  Tocilizumab  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Vardenafil  : May enhance the adverse/toxic effect of other Phosphodiesterase 5 Inhibitors.
  •  Verapamil  : CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil.
  •  Voriconazole  : May increase the serum concentration of Avanafil.

Food Interactions

  • When taken with a high-fat meal, time to maximum plasma concentration is prolonged- Tmax = 1 hour 20 minutes

Calculated Property

kind Value Source
logP 2.42 ALOGPS
logS -4.2 ALOGPS
Water Solubility 2.97e-02 g/l ALOGPS
logP 2.78 ChemAxon
IUPAC Name 4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide ChemAxon
Traditional IUPAC Name avanafil ChemAxon
Molecular Weight 483.951 ChemAxon
Monoisotopic Weight 483.17856544 ChemAxon
SMILES COC1=C(Cl)C=C(CNC2=C(C=NC(=N2)N2CCC[C@H]2CO)C(=O)NCC2=NC=CC=N2)C=C1 ChemAxon
Molecular Formula C23H26ClN7O3 ChemAxon
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 ChemAxon
InChIKey InChIKey=WEAJZXNPAWBCOA-INIZCTEOSA-N ChemAxon
Polar Surface Area (PSA) 125.39 ChemAxon
Refractivity 131.75 ChemAxon
Polarizability 50.87 ChemAxon
Rotatable Bond Count 9 ChemAxon
H Bond Acceptor Count 9 ChemAxon
H Bond Donor Count 3 ChemAxon
pKa (strongest acidic) 12.53 ChemAxon
pKa (strongest basic) 5.54 ChemAxon
Physiological Charge 0 ChemAxon
Number of Rings 4 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five 1 ChemAxon
Ghose Filter 0 ChemAxon
MDDR-Like Rule 1 ChemAxon

Affected organism

Humans and other mammals

Target within organism

  • cGMP-specific 3′,5′-cyclic phosphodiesterase : in Human