Ethyl 6-bromo-4-[(dimethylamino)methyl]-5-hydroxy-1-methyl-2-[(phenylthio)methyl]-1H-indole-3-carboxylate

531.89

477.41

1312995-182-4

93M09WW4RU

C152799

J - Antiinfectives for systemic use

80

4.4

White to off-white crystalline powder

1.37±0.1 g/cm3(Predicted)

591.8±50.0 °C(Predicted)

311.7±30.1 °C

1.620

"Expected to be poorly soluble"

1.34E-14mmHg at 25°C

P273, P391, P501

H400

The oral LD50 of umifenovir in mice and rats has been reported as 340-400 mg/kg and >3000 mg/kg, respectively. Chronic administration of doses 10-50 times the therapeutic human dose resulted in no pathological changes to animal subjects. Further information regarding the management of umifenovir overdose is unavailable.

Data regarding protein-binding of umifenovir are currently unavailable.

Umifenovir is currently licensed in China and Russia for the prophylaxis and treatment of influenza and other respiratory viral infections. It has demonstrated activity against a number of viruses and has been investigated in the treatment of _Flavivirus_, Zika virus, foot-and-mouth disease, Lassa virus, Ebola virus, and herpes simplex. In addition, it has shown _in vitro_ activity against hepatitis B and C viruses, chikungunya virus, reovirus, Hantaan virus, and coxsackie virus B5. Umifenovir is currently being investigated as a potential treatment and prophylactic agent for the prevention of COVID-19 caused by SARS-CoV-2 infections.

Umifenovir exerts its antiviral effects via both direct-acting virucidal activity and by inhibiting one (or several) stage(s) of the viral life cycle. Its broad-spectrum of activity covers both enveloped and non-enveloped RNA and DNA viruses. It is relatively well-tolerated and possesses a large therapeutic window - weight-based doses up to 100-fold greater than those used in humans failed to produce any pathological changes in test animals. Umifenovir does not appear to result in significant viral resistance. Instances of umifenovir-resistant influenza virus demonstrated a single mutation in the HA2 subunit of influenza hemagglutinin, suggesting resistance is conferred by prevention of umifenovir’s activity related to membrane fusion. The mechanism through which other viruses may become resistant to umifenovir requires further study.

Umifenovir is rapidly absorbed following oral administration, with an estimated T_max between 0.65-1.8 hours. The C_max has been estimated as 415 - 467 ng/mL and appears to increase linearly with dose, and the AUC_0-inf following oral administration has been estimated to be approximately 2200 ng/mL/h.|The major route of elimination is via the feces. Approximately 40% of an ingested dose is excreted unchanged, of which 38.9% is excreted in the bile and 0.12% excreted through the kidneys. The total recovery of parent drug and metabolites in the urine accounts for less than 1% of an ingested dose.|Data regarding the volume of distribution of umifenovir are currently unavailable.|In a study involving healthy male Chinese volunteers, the oral clearance of umifenovir was found to be 99 ± 34 L/h.

Umifenovir is highly metabolized in the body, primarily in hepatic and intestinal microsomess, with approximately 33 metabolites having been observed in human plasma, urine, and feces. The principal phase I metabolic pathways include sulfoxidation, N-demethylation, and hydroxylation, followed by phase II sulfate and glucuronide conjugation. In the urine, the major metabolites were sulfate and glucuronide conjugates, while the major species in the feces was unchanged parent drug (~40%) and the M10 metabolite (~3.0%). In the plasma, the principal metabolites are M6-1, M5, and M8 - of these, M6-1 appears of most importance given its high plasma exposure and long elimination half-life (~25h), making it a potentially important player in the safety and efficacy of umifenovir. Enzymes involved in the metabolism of umifenovir include members of the cytochrome P450 family (primarily CYP3A4), flavin-containing monooxygenase (FMO) family, and UDP-glucuronosyltransferase (UGT) family (specifically UGT1A9 and UGT2B7).|Arbidol has known human metabolites that include (2S,3S,4S,5R)-6-[6-bromo-4-[(dimethylamino)methyl]-3-ethoxycarbonyl-1-methyl-2-(phenylsulfanylmethyl)indol-5-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid.

The half-life of umifenovir following oral administration has been estimated to be between 17-21 hours. Serum half-lives of the M5, M6-1, and M8 metabolites were found to be 26.3 ± 5.9, 25.0 ± 5.4, and 25.7 ± 8.8, respectively.

Umifenovir is considered both a direct-acting antiviral (DAA) due to direct virucidal effects and a host-targeting agent (HTA) due to effects on one or multiple stages of viral life cycle (e.g. attachment, internalization), and its broad-spectrum antiviral activity is thought to be due to this dual activity. It is a hydrophobic molecule capable of forming aromatic stacking interactions with certain amino acid residues (e.g. tyrosine, tryptophan), which contributes to its ability to directly act against viruses. Antiviral activity may also be due to interactions with aromatic residues within the viral glycoproteins involved in fusion and cellular recognition, with the plasma membrane to interfere with clathrin-mediated exocytosis and intracellular trafficking, or directly with the viral lipid envelope itself (in enveloped viruses). Interactions at the plasma membrane may also serve to stabilize it and prevent viral entry (e.g. stabilizing influenza hemagglutinin inhibits the fusion step necessary for viral entry). Due to umifenovir’s ability to interact with both viral proteins and lipids, it may also interfere with later stages of the viral life cycle. Some virus families, such as _Flaviviridae_, replicate in a subcellular compartment called the membranous web - this web requires lipid-protein interactions that may be hindered by umifenovir. Similarly, viral assembly of hepatitis C viruses is contingent upon the assembly of lipoproteins, presenting another potential target.

1-methyl-2-((phenylthio)methyl)-3-carbethoxy-4-((dimethylamino)methyl)-5-hydroxy-6-bromoindole