Description
Merimepodib is an inhibitor of inosine-5''-monophosphate dehydrogenase (IMPDH; K
is = 7 and 10 nM for IMPDH type I and type II, respectively) with antiviral and immunosuppressant activities. It reduces Ebola, Lassa, chikungunya, Junin, and Zika virus titers
in vitro and inhibits Zika virus replication in Huh7 cells (EC
50 = 0.6 μM). Merimepodib inhibits the proliferation of PHA-stimulated T cells and SPAS-stimulated B cells (IC
50s = 104 and 132 nM, respectively), effects that can be reversed by guanosine but not adenosine .
In vivo, merimepodib (50 and 100 mg/kg) increases allograft survival in a murine skin transplantation model and prevents development of graft versus host disease (GVHD) in splenocyte allografted mice.
Uses
Inhibition of inosine monophosphate dehydrogenase (IMPDH), which has potential
antiviral, antiproliferative, antiparasitic, and immunosuppressive activity.
in vitro
vx-497 (mw 452.5) inhibited the proliferation of primary human, rat, mouse, and dog lymphocytes at concentrations of approximately 100 nm. the inhibitory effect of vx-497 on lymphocytes was reversed in the presence of exogenous guanosine, but not in the presence of adenosine or uridine, confirming that the antilymphocytic activity of vx-497 was specifically due to inhibition of impdh[1]. vx-497 was most potent against the first group of viruses on virus replication, which included hbv, hcmv, emcv, and rsv, with ic50 values of 0.38, 0.80, 1.0, and 1.14 μm, respectively [3].
in vivo
oral administration of vx-497 dose-dependently inhibited the primary igm antibody response, with an ed50 value of approximately 30-35 mg/kg in mice. single daily dosing of vx-497 was as effective as twice-daily dosing in this model of immune activation [1].in the skin transplant study, trunk skin grafts from balb/c mice were grafted onto c57bl/6 mice. administration of vx-497 twice daily until day 10 significantly prolonged graft survival to 13.2 ± 1.2 (p < 0.001, kaplan meier log-rank test) days in the 50 mg/kg group and 13.9 ± 1.0 (p < 0.001) days in the 85 mg/kg group [4].
References
[1]. jain j1, almquist sj,shlyakhter d,harding mw. vx-497: a novel, selective impdh inhibitor and immunosuppressive agent.j pharm sci.2001 may;90(5):625-37.
[2]. pimkin m1,markham gd. inosine 5'-monophosphate dehydrogenase.adv enzymol relat areas mol biol.2009;76:1-53.
[3]. markland w1,mcquaid tj,jain j,kwong ad. broad-spectrum antiviral activity of the imp dehydrogenase inhibitor vx-497: a comparison with ribavirin and demonstration of antiviral additivity with alpha interferon.antimicrob agents chemother.2000 apr;44(4):859-66.
[4]. decker cj1,heiser ad,chaturvedi pr,faust tj,ku g,moseley s,nimmesgern e. the novel impdh inhibitor vx-497 prolongs skin graft survival and improves graft versus host disease in mice.drugs exp clin res.2001;27(3):89-95.
