ChemicalBook Product Catalog API Nervous system drugs Amenamevir

Amenamevir

Product NameAmenamevir
CAS841301-32-4
MFC24H26N4O5S
MW482.55
EINECS
MOL File841301-32-4.mol

Chemical Properties

Density	1.360±0.06 g/cm3(Predicted)
storage temp.	Store at -20°C
solubility	DMF:PBS (pH 7.2) (1:20):0.04(Max Conc. mg/mL);0.08(Max Conc. mM) DMF:2.0(Max Conc. mg/mL);4.14(Max Conc. mM)
form	A solid
pka	12.60±0.70(Predicted)
color	White to off-white
InChIKey	MNHNIVNAFBSLLX-UHFFFAOYSA-N
SMILES	C1S(=O)(=O)CCC(C(N(C2=C(C)C=CC=C2C)CC(NC2=CC=C(C3N=CON=3)C=C2)=O)=O)C1

Usage And Synthesis

Description

Amenamevir is an antiviral inhibitor of herpes simplex virus 1 (HSV-1) helicase-primase complex activity. It inhibits recombinant HSV-1 helicase with an IC₅₀ value of 0.078 μM and recombinant HSV-1 primase when used at concentrations greater than or equal to 0.03 μM. Amenamevir inhibits replication of varicella-zoster virus (VZV), HSV-1, and HSV-2 in human embryonic fibroblast (HEF) cells (EC₅₀s = 0.047, 0.036, and 0.028 μM, respectively) and is not cytotoxic to HEF cells with a 50% cytotoxic concentration (CC₅₀) of greater than 30 μM. Amenamevir also inhibits replication of clinical VZV isolates in HEF cells (EC₅₀s = 0.038-0.10 μM). In vivo, it increases survival of cutaneously HSV-1-infected mice in a zosteriform-spread model of progressive HSV-1 infection (ED₅₀ = 1.9 mg/kg twice per day).

Uses

Amenamevir is a helicase-primase inhibitor which has potent antiviral activity against HSVs with an EC50 of 14 ng/mL.

Synthesis

he industrial synthesis of Amenamevir was first released by Kontani in their patent from 2005 (Scheme 2).17 Aniline 2 first underwent alkylation with ethyl bromoacetate 5 to intermediate 6, the amidation of 6 with synthesized acid chloride 7 in pyridine formed compound 8. 8 was then saponified and followed by condensation with aniline 10 to yield Amenamevir. The synthesis employs chlorinated solvents (DCM, CHCl3) during five steps. Based on the synthetic method of kontani, xumeng developed a superior strategy.
Different from Kontani, Xumeng first reacted acid 1 with oxalyl chloride, then followed by the nucleophilic addition with aniline 2 to provide amide intermediate 11. Then 11 sequentially subjected to N-alkylation, ester hydrolysis and amidation reaction to obtain Amenamevir.^[2]
Amenamevir synthesis

in vivo

Amenamevir (ASP2151) administration accelerates the reduction in virus titer in a dose-dependent manner in the range of 3 to 30 mg/kg/day. Amenamevir treatment decreases both lesion scores and HSV-1 titers in a dose-dependent manner, irrespective of the dosing interval. Based on the correlation curves, the PK parameters at which HSV-1 growth is completely suppressed by oral administration of Amenamevir are estimated to be 10,000 ng/mL or higher for the maximum concentration of drug in serum (C_max), 60 μg h/ml or higher for concentration-time curve over 24 h (AUC_24h), and 21 to 24 h for T_>100 . The mean concentration of Amenamevir in plasma at 5 days postinfection increases in a dose-dependent manner, with doses of 3 mg Amenamevir/g or higher significantly reducing the intradermal HSV-1 titer^[1].

IC 50

HSV-1: 7.7-20 ng/mL (IC₅₀); HSV-2: 15-58 ng/mL (IC₅₀)

References

[1] KOJI CHONO. ASP2151, a novel helicase-primase inhibitor, possesses antiviral activity against varicella-zoster virus and herpes simplex virus types 1 and 2.[J]. Journal of Antimicrobial Chemotherapy, 2010, 65 8: 1733-1741. DOI: 10.1093/jac/dkq198
[2] LI X, ZARGANES-TZITZIKAS T, KURPIEWSKA K, et al. Amenamevir by Ugi-4CR†[J]. Green Chemistry, 2023, 4: 1322-1325. DOI:10.1039/D2GC04869H.

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