Enterohepatic recirculation: a powerful incentive for drug discovery in the inosine monophosphate dehydrogenase field.
With the exception of organ transplant immunosuppression, the treatment of various IMPDH-dependent hyperproliferative diseases by MPA has failed due to the drug's EHC-induced GIT adverse effects. To influence its therapeutic index, novel formulations such as gastro-resistant MPA-Na (ERL080) or MPA/cholestyramine combinations have been developed. Structurally novel IMPDH inhibitors have been discovered based on high throughput screening (pyridazoles) and rational design (methoxyphenyloxazoles). The clinical data on methoxyphenyloxazole derivatives such as VX-497 that is not expected to undergo EHC, will bring improved understanding of the relationship between IMPDH blockade and GIT toxicity.
Papageorgiou
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Novartis Pharma AG, Transplantation Research, CH-4002 Basel, Switzerland. christos.papageorgiou@pharma.novartis.com
D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D008102:Liver Circulation / Q000187:drug effects / Q000502:physiology*; D013329:Structure-Activity Relationship
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007168:IMP Dehydrogenase