Inhibitors of dihydroorotate dehydrogenase

Abstract

Dihydroorotate dehydrogenase (DHODase) is the rate-limiting step in de novo pyrimidine biosynthesis, required for the proliferation of many cell types and for the growth of microorganisms. Inhibitors of this enzyme have potential as immunosuppressive agents for the prevention of organ transplant rejection, and for the treatment of autoimmune diseases such as rheumatoid arthritis (RA). Other possible applications are as anti-infective agents such as antimalarials and antibacterials. Two major chemical classes of mammalian DHODase inhibitors have been described in the literature, based on the drugs brequinar (BQR) and leflunomide (LFM). A few inhibitors of microbial enzymes have also been disclosed. Since DHODase inhibition has not yet been reviewed, this paper covers the patents and associated publications which have appeared during the past 13 years.