title: Discovery of N-[2-[2-[[3-methoxy-4-(5-oxazolyl)phenyl]amino]-5-oxazolyl]phenyl]-N-methyl-4- morpholineacetamide as a novel and potent inhibitor of inosine monophosphate dehydrogenase with excellent in vivo activity.
abstract: Inosine monophosphate dehydrogenase (IMPDH) is a key enzyme that is involved in the de novo synthesis of purine nucleotides. Novel 2-aminooxazoles were synthesized and tested for inhibition of IMPDH catalytic activity. Multiple analogues based on this chemotype were found to inhibit IMPDH with low nanomolar potency. One of the analogues (compound 23) showed excellent in vivo activity in the inhibition of antibody production in mice and in the adjuvant induced arthritis model in rats.
authors.forename: T G Murali
authors.initials: TG
authors.lastname: Dhar
authors.forename: Zhongqi
authors.initials: Z
authors.lastname: Shen
authors.forename: Junqing
authors.initials: J
authors.lastname: Guo
authors.forename: Chunjian
authors.initials: C
authors.lastname: Liu
authors.forename: Scott H
authors.initials: SH
authors.lastname: Watterson
authors.forename: Henry H
authors.initials: HH
authors.lastname: Gu
authors.forename: William J
authors.initials: WJ
authors.lastname: Pitts
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Fleener
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Rouleau
authors.forename: N Z
authors.initials: NZ
authors.lastname: Sherbina
authors.forename: Kim W
authors.initials: KW
authors.lastname: McIntyre
authors.forename: David J
authors.initials: DJ
authors.lastname: Shuster
authors.forename: Mark R
authors.initials: MR
authors.lastname: Witmer
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Tredup
authors.forename: Bang-Chi
authors.initials: BC
authors.lastname: Chen
authors.forename: Rulin
authors.initials: R
authors.lastname: Zhao
authors.forename: Mark S
authors.initials: MS
authors.lastname: Bednarz
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Cheney
authors.forename: John F
authors.initials: JF
authors.lastname: MacMaster
authors.forename: Laura M
authors.initials: LM
authors.lastname: Miller
authors.forename: Karen K
authors.initials: KK
authors.lastname: Berry
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Harper
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.forename: Diane L
authors.initials: DL
authors.lastname: Hollenbaugh
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Iwanowicz
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001169:Arthritis, Experimental / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D009025:Morpholines; C455799:N-(2-(2-((3-methoxy-4-(5-oxazolyl)phenyl)amino)-5-oxazolyl)phenyl)-N-methyl-4-morpholineacetamide; D010080:Oxazoles; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid