Identification of novel and potent isoquinoline aminooxazole-based IMPDH inhibitors.
Screening of our in-house compound collection led to the discovery of 5-bromo-6-amino-2-isoquinoline 1 as a weak inhibitor of IMPDH. Subsequent optimization of 1 afforded a series of novel 2-isoquinolinoaminooxazole-based inhibitors, represented by 17, with single-digit nanomolar potency against the enzyme.
Chen
Ping
P
Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA. ping.chen@bms.com
Norris
Derek
D
Haslow
Kristin D
KD
Murali Dhar
T G
TG
Pitts
William J
WJ
Watterson
Scott H
SH
Cheney
Daniel L
DL
Bassolino
Donna A
DA
Fleener
Catherine A
CA
Rouleau
Katherine A
KA
Hollenbaugh
Diane L
DL
Townsend
Robert M
RM
Barrish
Joel C
JC
Iwanowicz
Edwin J
EJ
D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D009243:NAD / Q000378:metabolism; D010080:Oxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007546:Isoquinolines; D010080:Oxazoles; D009243:NAD; D007168:IMP Dehydrogenase