VX-497: A novel, selective IMPDH inhibitor and immunosuppressive agent

Inosine monophosphate dehydrogenase (IMPDH) is an essential rate-limiting e nzyme in the purine metabolic pathway catalyzing the de novo synthesis of g uanine nucleotides required for lymphocyte proliferation. IMPDH has therefo re been an attractive target for developing immunosuppressive drugs (e.g., CellCept((R)) and mizoribine). Here we describe the immunosuppressive activ ity of VX-497, a nos el noncompetitive inhibitor of IMPDH. VX-497 (MW 452.5 ) is orally bioavailable and inhibits the proliferation of primary human, m ouse, rat, and dog lymphocytes at concentrations of similar to 100 nM. The inhibitory effect of VX-497 on lymphocytes is reversed in the presence of e xogenous guanosine, but not in the presence of adenosine or uridine, confir ming that the antilymphocytic activity of VX-497 is specifically due to inh ibition of IMPDH. The antiproliferative effect of VX-497 in cells is also r eversed within 48 h of its removal. Based on evaluation of VX-497 in severa l lymphoid and nonlymphoid cells, the antiproliferative effect of VX-497 is observed to be most pronounced on lymphoid and keratinocyte cells as compa red with fibroblasts. In vivo, oral administration of VX-491 inhibits the p rimary IgM antibody response in a close-dependent manner, with an ED50 valu e of similar to 30-35 mg/kg in mice. Single daily dosing of VX-491 is obser ved to be as effective as twice-daily dosing in this model of immune activa tion. These studies demonstrate that VX-497 is a potent, specific, and reve rsible IMPDH inhibitor that selectively inhibits lymphocyte proliferation. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pha rm Sci 90:626-637, 2001.