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 potential applications as antitumour and antimicrobial agents. The clinical value of the most potent and specific inhibitor of IMPDH, mycophenolic acid, is limited by its rapid metabolism in vivo to an inactive glucuronide derivative. There is, therefore, a considerable incentive to develop structurally novel, preferably non-nucleoside, inhibitors with greater metabolic stability than mycophenolic acid. Here, we describe a high throughput screen for inhibitors of IMPDH, which facilitated the discovery of a single novel non-nucleoside inhibitor from a collection of approximately 80,000 compounds. The inhibitor is a pyridazine, which, like mycophenolic acid, exerts uncompetitive 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 conversion of IMP to xanthosine monophosphate. Chemical modification of the lead 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 the compounds was available in sufficient quantity to demonstrate highly effective immunosuppressive activity in a model of delayed type hypersensitivity in mice. To our knowledge, the novel pyridazines described in this report 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.
Franklin
T J
TJ
Zeneca Pharmaceuticals, Macclesfield, Cheshire, UK.
Morris
W P
WP
Jacobs
V N
VN
Culbert
E J
EJ
Heys
C A
CA
Ward
W H
WH
Cook
P N
PN
Jung
F
F
Plé
P
P
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D007166:Immunosuppressive Agents; D011724:Pyridazines; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase