Merimepodib

Merimepodib (VX-497, VI-21497, MMPD) is a potent, selective, reversible, uncompetitive IMPDH inhibitor with broad-spectrum antiviral activity; inhibits HBV, HCMV, RSV and HSV-1 with IC50 of 0.4, 0.8, 1.1 and 6.3 uM, also inhibits BVDV, VEEV, Coxsackie B3 and Dengue virus with IC50 at low uM level; Merimepodib is 17- to 186-fold more potent than ribavirin against HBV, HCMV, RSV, HSV-1, parainfluenza-3 virus, EMCV, and VEEV infections in cultured cells, also demonstrates additivity when coapplied with IFN-alpha.HCV Infection Discontinued(In Vitro):VX-497 has antiproliferative effect on lymphoid and keratinocyte cells. The antiproliferative effect of VX-497 in cells is reversed within 48 h of its removal. VX-497 has intermediate antiviral activity against a second group of viruses, which includes HSV-1, parainfluenza-3 virus, BVDV, VEEV, and dengue virus, with IC50s ranging from 6 to 19 μM. VX-497 is 100-fold more potent, with an IC50 of 380 nM and a corresponding CC50 of 5.2 μM, for a therapeutic index of 14. The antiviral activity of VX-497 in HepG2.2.2.15 cells is reversed threefold by the addition of guanosine.\n(In Vivo):Oral administration of VX-497 inhibits the primary IgM antibody response in a dose-dependent manner, with an ED50 value of appr 30-35 mg/kg in mice. Single daily dosing of VX-497 is observed to be as effective as twice-daily dosing in this model of immune activation. GVHD developed in the vehicle-treated allografted F1 mice and treatment with VX-497 improved all manifestations of the disease significantly. The 2.9-fold increase in spleen weight in allografted animals is reduced to a 1.6-fold increase in the VX-497-treated mice. Serum IFN-gamma levels are increased 54-fold in the vehicle group while there is a 7.4-fold increase in VX-497-treated animals.