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.
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.
Dhar
T G Murali
TG
Shen
Zhongqi
Z
Guo
Junqing
J
Liu
Chunjian
C
Watterson
Scott H
SH
Gu
Henry H
HH
Pitts
William J
WJ
Fleener
Catherine A
CA
Rouleau
Katherine A
KA
Sherbina
N Z
NZ
McIntyre
Kim W
KW
Shuster
David J
DJ
Witmer
Mark R
MR
Tredup
Jeffrey A
JA
Chen
Bang-Chi
BC
Zhao
Rulin
R
Bednarz
Mark S
MS
Cheney
Daniel L
DL
MacMaster
John F
JF
Miller
Laura M
LM
Berry
Karen K
KK
Harper
Timothy W
TW
Barrish
Joel C
JC
Hollenbaugh
Diane L
DL
Iwanowicz
Edwin J
EJ
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
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