A novel series of non-nucleoside inhibitors of inosine 5 '-monophosphate dehydrogenase with immunosuppressive activity

Inhibitors of inosine 5'-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) are effective immunosuppressive drugs that may also have additional potenti al applications as antitumour and antimicrobial agents. The clinical value of the most potent and specific inhibitor of IMPDH, mycophenolic acid, is l imited by its rapid metabolism in vivo to an inactive glucuronide derivativ e. There is, therefore, a considerable incentive to develop structurally no vel, preferably non-nucleoside, inhibitors with greater metabolic stability than mycophenolic acid. Here, we describe a high throughput screen for inh ibitors of IMPDH, which facilitated the discovery of a single novel non-nuc leoside inhibitor from a collection of approximately 80,000 compounds. The inhibitor is a pyridazine, which, like mycophenolic acid, exerts uncompetit ive inhibition of IMPDH. Analysis of the enzyme kinetics suggests that the inhibitory action of the pyridazine is similar to that of mycophenolic acid , which involves trapping of a covalent intermediate formed during the conv ersion of IMP to xanthosine monophosphate. Chemical modification of the lea d compound resulted in pyridazine derivatives with enhanced potency against IMPDH and guanine nucleotide synthesis in cultured cells in vitro and also against guanine nucleotide synthesis in the mouse spleen in vivo. One of t he compounds was available in sufficient quantity to demonstrate highly eff ective immunosuppressive activity in a model of delayed type hypersensitivi ty in mice. To our knowledge, the novel pyridazines described in this repor t represent the first non-nucleoside uncompetitive inhibitors of IMPDH with immunosuppressive activity since the discovery of the inhibitory activity of mycophenolic acid and its derivatives thirty years ago. (C) 1999 Elsevie r Science Inc.