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

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 Ki 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 inhib-itory activity of VX-148 is alleviated in the presence of exoge-nous guanosine. VX-148 does not inhibit proliferation of non-lymphoid cell types such as fibroblasts, indicating selectivity for inhibition of IMPDH activity. VX-148 is orally bioavailable in rat