title: Structure-activity relationships for inhibition of inosine monophosphate dehydrogenase by nuclear variants of mycophenolic acid.
abstract: Structure-activity relationships in the region of the phthalide ring of 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. Replacement of the ring by acyclic substituents also indicated a strong sensitivity to steric bulk. A phenolic hydroxyl group, with an adjacent hydrogen bond acceptor, was found to be essential for high potency. The aromatic methyl group was essential for activity; the methoxyl group could be replaced by ethyl to give a compound with 2-4 times the potency of mycophenolic acid in vitro and in vivo.
authors.affiliation: Institute of Organic Chemistry, Syntex Research, Palo Alto, California 94304, USA.
authors.forename: P H
authors.initials: PH
authors.lastname: Nelson
authors.forename: S F
authors.initials: SF
authors.lastname: Carr
authors.forename: B H
authors.initials: BH
authors.lastname: Devens
authors.forename: E M
authors.initials: EM
authors.lastname: Eugui
authors.forename: F
authors.initials: F
authors.lastname: Franco
authors.forename: C
authors.initials: C
authors.lastname: Gonzalez
authors.forename: R C
authors.initials: RC
authors.lastname: Hawley
authors.forename: D G
authors.initials: DG
authors.lastname: Loughhead
authors.forename: D J
authors.initials: DJ
authors.lastname: Milan
authors.forename: E
authors.initials: E
authors.lastname: Papp
authors.forename: J W
authors.initials: JW
authors.lastname: Patterson
authors.forename: S
authors.initials: S
authors.lastname: Rouhafza
authors.forename: E B
authors.initials: EB
authors.lastname: Sjogren
authors.forename: D B
authors.initials: DB
authors.lastname: Smith
authors.forename: R A
authors.initials: RA
authors.lastname: Stephenson
authors.forename: F X
authors.initials: FX
authors.lastname: Talamas
authors.forename: A M
authors.initials: AM
authors.lastname: Waltos
authors.forename: R J
authors.initials: RJ
authors.lastname: Weikert
authors.forename: J C
authors.initials: JC
authors.lastname: Wu
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D005260:Female; D006462:Hemolytic Plaque Technique; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D011994:Recombinant Proteins; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid