STRUCTURE-ACTIVITY-RELATIONSHIPS FOR INHIBITION OF INOSINE MONOPHOSPHATE DEHYDROGENASE BY NUCLEAR VARIANTS OF MYCOPHENOLIC-ACID

Structure-activity relationships in the region of the phthalide ring o f the inosine monophosphate dehydrogenase inhibitor mycophenolic acid have been explored. Replacement of the lactone ring with other cyclic moieties resulted in loss of potency, especially for larger groups. Re placement of the ring by acyclic substituents also indicated a strong sensitivity to steric bulk. A phenolic hydroxyl group, with an adjacen t hydrogen bond acceptor, was found to be essential for high potency. The aromatic methyl group was essential for activity; the methoxyl gro up could be replaced by ethyl to give a compound with 2-4 times the po tency of mycophenolic acid in vitro and in vivo.