Verdinexor (KPT-335) Chemical Properties

Density 

1.49±0.1 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

≥44.2 mg/mL in DMSO; insoluble in H2O; ≥2.31 mg/mL in EtOH with ultrasonic

form 

solid

pka

10.04±0.43(Predicted)

color 

Light yellow to yellow

InChI

InChI=1S/C18H12F6N6O/c19-17(20,21)12-7-11(8-13(9-12)18(22,23)24)16-26-10-30(29-16)6-4-15(31)28-27-14-3-1-2-5-25-14/h1-10H,(H,25,27)(H,28,31)/b6-4-

InChIKey

OPAKEJZFFCECPN-XQRVVYSFSA-N

SMILES

C(NNC1=NC=CC=C1)(=O)/C=C\N1C=NC(C2=CC(C(F)(F)F)=CC(C(F)(F)F)=C2)=N1

CAS DataBase Reference

1392136-43-4

Verdinexor (KPT-335) Usage And Synthesis

Uses

Verdinexor is a potent and selective SINE inhibitor, shown to be effective in treating influenza A virus infection in mice and ferret models.

Biological Activity

verdinexor (kpt-335) is a potent and selective inhibitor of nuclear export [1].nuclear export (sine) is mainly mediated by exportin 1 (xpo1) and mediates specific proteins out of the nucleus, which plays an important role in the regulation of proliferation and the cell cycle [2].verdinexor (kpt-335) is a potent and selective sine inhibitor that acts as an antiviral drug. in a549 cells inoculated with the influenza a and b virus, verdinexor effectively inhibited the replication of the influenza a and b virus strains tested. verdinexor (1 μm) caused the accumulation of vrnps in the nuclei and altered the localization of viral ns1. also, verdinexor increased nuclear negative-sense vrna by 56.6-fold and significantly reduced cytoplasmic negative-sense vrna, which suggested that verdinexor blocked vrnp nuclear export. in 293t cells, verdinexor inhibited xpo1-nep binding [1].in mice infected with influenza virus a, verdinexor significantly reduced lung influenza virus a titers. verdinexor also reduced the expression of proinflammatory cytokines tumor necrosis factor alpha, interleukin-6, interleukin-1β and gamma interferon. in mice infected with a lethal dose, verdinexor inhibited virus penetration of the respiratory tract and virus spread in the lungs [1]. in companion dogs with b- and t-cell lymphomas, verdinexor showed potent cytotoxic activity [2].

Synthesis

Example 3: Synthesis of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N'-(pyridin-2-yl)acrylhydrazide hydrochloride (1-4). To a 500 mL three-necked round-bottomed flask was added a suspension of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylhydrazide (10 g, 1.0 equiv) in 1:1 CH2Cl2:AcOEt (200 mL). 2-Hydrazinylpyridine (3.11 g) was added at -40 °C. T3P (50% ethyl acetate solution, 21.75 g) was added dropwise followed by DIPEA (7.36 g). The reaction mixture was stirred at -40 °C for 30 min and then concentrated under reduced pressure at 35 °C, 20 mmHg. A crude brown oil was obtained, which was purified by column chromatography (eluent: CH2Cl2 solution of 1.3% MeOH). The fractions containing the target compound were combined to give 6.0 g (yield: 48%) of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N'-(pyridin-2-yl)acrylhydrazide.1H NMR (400 MHz, DMSO-d6) δ: 10.41 (s, 1H), 9.66 (s, 1H) , 8.59 (s, 1H), 8.53 (s, 2H), 8.28 (s, 1H), 8.06-8.08 (d, J = 5.2 Hz, 1H), 7.48-7.53 (m, 1H), 7.49-7.52 (d, J = 10.4 Hz, 1H), 6.71-6.75 (m, 1H), 6.66-6.68 (d, J = 8.4 Hz, 1H), 6.07-6.09 (d, J = 10.4 Hz, 1H).LCMS (C18H12F6N6O [M+H]+) Predicted: 443.33, Measured: 443.44 (RT 2.45 min, purity: 100%).

storage

Store at -20°C

References

[1]. perwitasari o, johnson s, yan x, et al. verdinexor, a novel selective inhibitor of nuclear export, reduces influenza a virus replication in vitro and in vivo. j virol, 2014, 88(17): 10228-10243.
[2]. gravina gl, senapedis w, mccauley d, et al. nucleo-cytoplasmic transport as a therapeutic target of cancer. j hematol oncol, 2014, 7: 85.

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