Amenamevir
[CAS# 841301-32-4]

Identification

• Classification: API >> Synthetic anti-infective drugs >> Antiviral drugs
• Name: Amenamevir
• Synonyms: N-(2,6-Dimethylphenyl)tetrahydro-N-[2-[[4-(1,2,4-oxadiazol-3-yl)phenyl]amino]-2-oxoethyl]-2H-thiopyran-4-carboxamide 1,1-dioxide; ASP 2151
• Molecular Formula: C₂₄H₂₆N₄O₅S
• Molecular Weight: 482.55
• CAS Registry Number: 841301-32-4
• SMILES: CC1=C(C(=CC=C1)C)N(CC(=O)NC2=CC=C(C=C2)C3=NOC=N3)C(=O)C4CCS(=O)(=O)CC4

Properties

• Solubility: Practically insoluble (0.011 g/L) (25 ºC), Calc.^*
• Density: 1.360±0.06 g/cm³ (20 ºC 760 Torr), Calc.^*
• Index of refraction: 1.623 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319-H335
• Precautionary Statements: P261-P305+P351+P338

Discovory and Applicatios

Amenamevir is an orally active antiviral compound developed for the treatment of herpesvirus infections. It belongs to the class of helicase-primase inhibitors and was specifically designed to inhibit viral DNA replication in herpesviruses such as varicella-zoster virus (VZV) and herpes simplex virus (HSV) types 1 and 2. Its development addressed the need for alternative antiviral agents distinct from nucleoside analogs like acyclovir, especially for drug-resistant strains.

The mechanism of action of amenamevir is based on its selective inhibition of the helicase-primase complex, an essential component of herpesvirus DNA replication machinery. This complex consists of three subunits that unwind DNA and initiate primer synthesis. By binding to the helicase-primase complex, amenamevir disrupts the separation of double-stranded viral DNA and the formation of RNA primers, thereby halting the replication process. This mechanism differs fundamentally from nucleoside analogs, which inhibit viral DNA polymerase after being incorporated into the growing DNA strand.

Amenamevir demonstrates potent antiviral activity against VZV and HSV in vitro and in animal models. Its efficacy has been confirmed in clinical studies for the treatment of herpes zoster (shingles). It has shown comparable or superior efficacy to existing antivirals in reducing the time to lesion healing and the duration of acute pain. One of the key advantages of amenamevir is its once-daily oral dosing regimen due to its favorable pharmacokinetic profile, which includes a long half-life and high plasma concentrations maintained over 24 hours.

The drug is metabolized primarily in the liver, with its main metabolic pathway involving cytochrome P450 enzymes, particularly CYP3A. It is excreted via both renal and hepatic routes. Amenamevir’s pharmacokinetics are not significantly altered by mild to moderate renal impairment, which supports its use in a broader patient population without extensive dose adjustments.

Adverse effects reported during clinical trials have been generally mild and transient. These include headache, gastrointestinal discomfort, and liver enzyme elevation, although the overall safety profile is considered favorable. Amenamevir does not require activation by viral thymidine kinase, which contributes to its activity against strains resistant to acyclovir and similar nucleoside analogs.

Amenamevir has been approved for medical use in Japan for the treatment of herpes zoster. It represents a novel class of antivirals that expands the options for managing herpesvirus infections, particularly in cases where conventional therapies are ineffective or poorly tolerated.

In summary, amenamevir is a helicase-primase inhibitor used for the treatment of herpes zoster. It offers an alternative antiviral mechanism distinct from nucleoside analogs, with proven clinical efficacy, once-daily oral administration, and a favorable safety and pharmacokinetic profile.

References

2023. Accelerating antiviral drug discovery: lessons from COVID-19. Nature reviews. Drug discovery, 22(7).
DOI: 10.1038/s41573-023-00692-8

2024. Efficacy and Safety of Amenamevir, a Helicase-Primase Inhibitor for the Treatment of Acyclovir-Resistant Herpes Simplex Virus 1 Keratitis. Cornea, 43(7).
DOI: 10.1097/ico.0000000000003553

2013. Synergistic activity of amenamevir (ASP2151) with nucleoside analogs against herpes simplex virus types 1 and 2 and varicella-zoster virus. Antiviral Research, 97(2).
DOI: 10.1016/j.antiviral.2012.12.006