Inosine monophosphate dehydrogenase (IMPDH) is an essential rate-limiting enzyme in the purine metabolic pathway, catalyzing the de novo synthesis of guanine nucleotides required for lymphocyte proliferation. IMPDH has therefore been an attractive target for developing immunosuppressive drugs (e.g., CellCept and mizoribine). Here we describe the immunosuppressive activity of VX-497, a novel noncompetitive inhibitor of IMPDH. VX-497 (MW 452.5) is orally bioavailable and inhibits the proliferation of primary human, mouse, rat, and dog lymphocytes at concentrations of approximately 100 nM. The inhibitory effect of VX-497 on lymphocytes is reversed in the presence of exogenous guanosine, but not in the presence of adenosine or uridine, confirming that the antilymphocytic activity of VX-497 is specifically due to inhibition of IMPDH. The antiproliferative effect of VX-497 in cells is also reversed within 48 h of its removal. Based on evaluation of VX-497 in several lymphoid and nonlymphoid cells, the antiproliferative effect of VX-497 is observed to be most pronounced on lymphoid and keratinocyte cells as compared with fibroblasts. In vivo, oral administration of VX-497 inhibits the primary IgM antibody response in a dose-dependent manner, with an ED(50) value of approximately 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. These studies demonstrate that VX-497 is a potent, specific, and reversible IMPDH inhibitor that selectively inhibits lymphocyte proliferation.
Copyright 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association.