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Merimepodib(VX-497) is a novel, noncompetitive and orally bioavailable inhibitor of Inosine monophosphate dehydrogenase (IMPDH) [1]. IMPDH is anenzymethat convertsinosine monophosphatetoxanthosine monophosphate. IMPDH is associated withcell proliferation, making it a possible target forcancerchemotherapy [2].

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].

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