Inosine 5'-monophosphate dehydrogenase inhibitors for the treatment of autoimmune diseases

Abstract

Inosine 5'-monophosphate dehydrogenase (IMPDH) is a key enzyme in the de novo biosynthesis of guanine nucleotides. Proliferation of T- and B-lymphocytes, a hallmark of many autoimnunne diseases, is heavily dependent on access to a large pool of guanine nucleotides. To support this activity IMPDH is upregulated. The clinical benefit observed with mnycophenolic acid, a potent IMPDH inhibitor, in a number of autoimmune diseases, including those associated with organ transplantation, rheumatoid arthritis, psoriasis, systemic lupus erythenmatosus and inflammatory bowel disease, has validated IMPDH as an immunosuppressive target, and triggered the search from the pharmaceutical industry for IMPDH inhibitors with best-in-class status. This review will highlight recent advances in the IMPDH field, with a focus on the discovery and development of non-nucleoside IMPDH inhibitors.