Avanafil
[CAS# 330784-47-9]

Identification

• Classification: Biochemical >> Inhibitor >> Metabolism >> PDE inhibitor
• Name: Avanafil
• Synonyms: 4-[(3-Chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide; (S)-2-(2-Hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-pyrimidinylmethyl)carbamoyl]pyrimidine
• Molecular Formula: C₂₃H₂₆ClN₇O₃
• Molecular Weight: 483.95
• CAS Registry Number: 330784-47-9 (647841-09-6)
• EC Number: 841-424-3
• SMILES: COC1=C(C=C(C=C1)CNC2=NC(=NC=C2C(=O)NCC3=NC=CC=N3)N4CCC[C@H]4CO)Cl

Properties

• Solubility: 10mM (DMSO)
• Density: 1.372

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H315-H319-H335
• Safety Statements: P261-P264-P264+P265-P271-P280-P302+P352-P304+P340-P305+P351+P338-P319-P321-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2	H319
Eye irritation	Eye Irrit.	2A	H319

Discovery and Applications

Avanafil is a modern medication used to treat erectile dysfunction (ED) that has a rapid onset of action and fewer side effects than earlier drugs of the same class. Avanafil was developed by Mitsubishi Tanabe Pharma and later co-marketed by VIVUS, Inc. under the brand name Stendra (or Spedra in Europe). It was developed to address the limitations of existing PDE5 inhibitors such as sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra), with the specific goal of faster onset of action and fewer side effects. In April 2012, avanafil was approved by the U.S. FDA, becoming the fourth PDE5 inhibitor available for the treatment of erectile dysfunction.

The development of the drug involved a relentless effort in medicinal chemistry to design a molecule that could selectively and effectively bind to the PDE5 enzyme, which plays an important role in regulating blood flow to the penis. Avanafil works by inhibiting the PDE5 enzyme, which is responsible for breaking down cyclic guanosine monophosphate (cGMP). cGMP is a key mediator of relaxation of the smooth muscle cells of the corpus cavernosum, which results in increased blood flow and promotes erections. By blocking PDE5, avanafil increases cGMP levels, which in turn enhances and prolongs erectile responses to sexual stimulation.

Avanafil has a rapid onset of action, typically within 15 to 30 minutes after oral administration, and its effects can last up to 6 hours. This rapid response makes it a particularly attractive option for patients seeking spontaneous sexual activity.

Avanafil is rapidly absorbed, with peak plasma concentrations within 30 to 45 minutes. It is primarily metabolized in the liver by cytochrome P450 enzymes, particularly CYP3A4. The drug and its metabolites are excreted in the urine and feces. Avanafil has a half-life of approximately 5 hours, which balances its efficacy with a relatively short duration of adverse effects.

The primary use of avanafil is in the treatment of erectile dysfunction. Its efficacy in promoting erections has been demonstrated in numerous clinical trials, and it is effective in treating a variety of ED etiologies, including psychological, physiological, and mixed.

Compared to other PDE5 inhibitors, avanafil has a rapid onset and shorter duration of action, making it convenient to use and improving patient compliance. It can make sexual activity more spontaneous, without the need for extensive planning.

Compared to older PDE5 inhibitors, avanafil has fewer side effects. Common side effects include headache, flushing, nasal congestion, and back pain, but these are generally mild and transient. Its selectivity for PDE5 compared to other PDE enzymes reduces the potential for adverse effects related to the cardiovascular system.

Researchers are exploring the potential to combine avanafil with other treatments for erectile dysfunction or related conditions. This could enhance its therapeutic effects or expand its use to a wider patient population.

References

2024. An overview on pharmaceutical applications of phosphodiesterase enzyme 5 (PDE5) inhibitors. Molecular Diversity, 28(5).
DOI: 10.1007/s11030-024-11016-2

2024. Avanafil Mitigates Testicular Ischemia/Reperfusion Injury via NLRP3 Pathway Modulation in Rats. Reproductive sciences (Thousand Oaks, Calif.), 31(9).
DOI: 10.1007/s43032-024-01696-4