Vol. 302, Issue 3, 1272-1277, September 2002

Characterization of Pharmacological Efficacy of VX-148, a New, Potent Immunosuppressive Inosine 5'-Monophosphate Dehydrogenase Inhibitor

Jugnu Jain, Susan J. Almquist, Angela D. Heiser, Dina Shlyakhter, Eduardo Leon, Christine Memmott, Cameron Stuver Moody, Elmar Nimmesgern and Caroline Decker

Vertex Pharmaceuticals, Inc., Cambridge, Massachusetts

Inosine 5'-monophosphate dehydrogenase (IMPDH) enzyme catalyzes the rate-limiting step in the de novo biosynthesis of guanine nucleotides. Proliferation of lymphocytes is critically dependent on this de novo nucleotide synthesis pathway. Hence, IMPDH is an attractive target for the development of immunosuppressive drugs. VX-148 is a novel, uncompetitive IMPDH inhibitor with a K_i value of 6 nM against IMPDH type II enzyme. VX-148 is slightly more potent than mycophenolic acid and VX-497 in inhibiting the proliferation of mitogen-stimulated primary human lymphocytes (IC₅₀ value of ~80 nM). The inhibitory activity of VX-148 is alleviated in the presence of exogenous guanosine. VX-148 does not inhibit proliferation of nonlymphoid cell types such as fibroblasts, indicating selectivity for inhibition of IMPDH activity. VX-148 is orally bioavailable in rats and mice; oral administration of VX-148 inhibits primary antibody response in mice in a dose-dependent manner with an ED₅₀ value of 38 mg/kg b.i.d. VX-148 significantly prolongs skin graft survival at 100 mg/kg b.i.d. in mice. These results demonstrate that VX-148 is a potent and specific IMPDH inhibitor with a favorable pharmacokinetic profile and good pharmacological activity in mice, and thus support development of VX-148 as an immunosuppressive drug.