ST-193 - CAS 489416-12-8
Category: Inhibitor
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Molecular Formula:
C24H25N3O
Molecular Weight:
371.47
COA:
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Targets:
Others
Description:
ST-193 is a potent, broad-spectrum small-molecule inhibitor of arenavirus entry and exhibits submicromolar antiviral activity in vitro. ST-193 inhibits Guanarito, Junin, Lassa and Machupo virus with IC50 values of 0.44, 0.62, 1.4 and 3.1 nM, respectively.
Synonyms:
1-(4-methoxyphenyl)-N-[(4-propan-2-ylphenyl)methyl]benzimidazol-5-amine; ST-193; ST 193; ST193
Solubility:
DMSO: ≥ 150 mg/mL
Storage:
Store in a cool and dry place (or refer to the Certificate of Analysis).
MSDS:
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Boiling Point:
562.5±60.0 ℃ at 760 Torr
Density:
1.12±0.1 g/cm3
InChIKey:
JPSZEXYTKSIPDW-UHFFFAOYSA-N
InChI:
1S/C24H25N3O/c1-17(2)19-6-4-18(5-7-19)15-25-20-8-13-24-23(14-20)26-16-27(24)21-9-11-22(28-3)12-10-21/h4-14,16-17,25H,15H2,1-3H3
Canonical SMILES:
CC(C)C1=CC=C(C=C1)CNC2=CC3=C(C=C2)N(C=N3)C4=CC=C(C=C4)OC
1.Evaluation of Lassa antiviral compound ST-193 in a guinea pig model.
Cashman KA;Smith MA;Twenhafel NA;Larson RA;Jones KF;Allen RD 3rd;Dai D;Chinsangaram J;Bolken TC;Hruby DE;Amberg SM;Hensley LE;Guttieri MC Antiviral Res. 2011 Apr;90(1):70-9. doi: 10.1016/j.antiviral.2011.02.012. Epub 2011 Mar 1.
Lassa virus (LASV), a member of the Arenaviridae family, causes a viral hemorrhagic fever endemic to West Africa, where as many as 300,000 infections occur per year. Presently, there are no FDA-approved LASV-specific vaccines or antiviral agents, although the antiviral drug ribavirin has shown some efficacy. A recently identified small-molecule inhibitor of arenavirus entry, ST-193, exhibits submicromolar antiviral activity in vitro. To determine the antiviral utility of ST-193 in vivo, we tested the efficacy of this compound in the LASV guinea pig model. Four groups of strain 13 guinea pigs were administered 25 or 80 mg/kg ST-193, 25 mg/kg of ribavirin, or the vehicle by the intraperitoneal (i.p.) route before infection with a lethal dose of LASV, strain Josiah, and continuing once daily for 14 days. Control animals exhibited severe disease, becoming moribund between days 10 and 15 postinfection. ST-193-treated animals exhibited fewer signs of disease and enhanced survival when compared to the ribavirin or vehicle groups. Body temperatures in all groups were elevated by day 9, but returned to normal by day 19 postinfection in the majority of ST-193-treated animals. ST-193 treatment mediated a 2-3-log reduction in viremia relative to vehicle-treated controls.
2.pH-induced activation of arenavirus membrane fusion is antagonized by small-molecule inhibitors.
York J;Dai D;Amberg SM;Nunberg JH J Virol. 2008 Nov;82(21):10932-9. doi: 10.1128/JVI.01140-08. Epub 2008 Sep 3.
The arenavirus envelope glycoprotein (GPC) mediates viral entry through pH-induced membrane fusion in the endosome. This crucial process in the viral life cycle can be specifically inhibited in the New World arenaviruses by the small-molecule compound ST-294. Here, we show that ST-294 interferes with GPC-mediated membrane fusion by targeting the interaction of the G2 fusion subunit with the stable signal peptide (SSP). We demonstrate that amino acid substitutions at lysine-33 of the Junín virus SSP confer resistance to ST-294 and engender de novo sensitivity to ST-161, a chemically distinct inhibitor of the Old World Lassa fever virus. These compounds, as well as a broadly active inhibitor, ST-193, likely share a molecular target at the SSP-G2 interface. We also show that both ST-294 and ST-193 inhibit pH-induced dissociation of the G1 receptor-binding subunit from GPC, a process concomitant with fusion activation. Interestingly, the inhibitory activity of these molecules can in some cases be overcome by further lowering the pH used for activation. Our results suggest that these small molecules act to stabilize the prefusion GPC complex against acidic pH. The pH-sensitive interaction between SSP and G2 in GPC represents a robust molecular target for the development of antiviral compounds for the treatment of arenavirus hemorrhagic fevers.
3.Identification of a broad-spectrum arenavirus entry inhibitor.
Larson RA;Dai D;Hosack VT;Tan Y;Bolken TC;Hruby DE;Amberg SM J Virol. 2008 Nov;82(21):10768-75. doi: 10.1128/JVI.00941-08. Epub 2008 Aug 20.
Several arenaviruses, including Lassa virus (LASV), are causative agents of hemorrhagic fever, for which effective therapeutic options are lacking. The LASV envelope glycoprotein (GP) gene was used to generate lentiviral pseudotypes to identify small-molecule inhibitors of viral entry. A benzimidazole derivative with potent antiviral activity was identified from a high-throughput screen utilizing this strategy. Subsequent lead optimization for antiviral activity identified a modified structure, ST-193, with a 50% inhibitory concentration (IC(50)) of 1.6 nM against LASV pseudotypes. ST-193 inhibited pseudotypes generated with other arenavirus envelopes as well, including the remaining four commonly associated with hemorrhagic fever (IC(50)s for Junín, Machupo, Guanarito, and Sabiá were in the 0.2 to 12 nM range) but exhibited no antiviral activity against pseudotypes incorporating either the GP from the LASV-related arenavirus lymphocytic choriomeningitis virus (LCMV) or the unrelated G protein from vesicular stomatitis virus, at concentrations of up to 10 microM. Determinants of ST-193 sensitivity were mapped through a combination of LASV-LCMV domain-swapping experiments, genetic selection of viral variants, and site-directed mutagenesis.
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CAS 489416-12-8 ST-193

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