6-Position optimization of tricyclic 4-quinolone-based inhibitors of glycogen synthase kinase-3β: discovery of nitrile derivatives with picomolar potency.
We previously disclosed tricylic, 6-carboxylic acid-bearing 4-quinolones as GSK-3β inhibitors. Herein we discuss the optimization of this series to yield a series of more potent 6-nitrile analogs with insignificant anti-microbial activity. Finally, kinase profiling indicated that members of this class were highly specific GSK-3 inhibitors.
ActivX Biosciences, Inc., 11025 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Bei
B
Li
Oana M
OM
Cociorva
Tyzoon
T
Nomanbhoy
Qiang
Q
Li
Kai
K
Nakamura
Masahiro
M
Nomura
Kyoko
K
Okada
Kazuhiro
K
Yumoto
Marek
M
Liyanage
Melissa C
MC
Zhang
Arwin
A
Aban
Anna Katrin
AK
Szardenings
John W
JW
Kozarich
Yasushi
Y
Kohno
Kevin R
KR
Shreder
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry*; D011807:Quinolizines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D009570:Nitriles; D011807:Quinolizines; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3