The development of potent and selective bisarylmaleimide GSK3 inhibitors.
Many 3-aryl-4-(1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl)maleimides exhibit potent GSK3 inhibitory activity (<100 nM IC(50)), although few show significant selectivity (>100x) versus CDK2, CDK4, or PKCbetaII. However, combining 3-(imidazo[1,2-a]pyridin-3-yl), 3-(pyrazolo[1,5-a]pyridin-3-yl) or aza-analogs with a 4-(2-acyl-(1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl)) group on the maleimide resulted in very potent inhibitors of GSK3 (</=5 nM) with >160 to >10,000-fold selectivity versus CDK2/4 and PKCbetaII. These compounds also inhibited tau phosphorylation in cells and were effective in lowering plasma glucose in a rat model of type 2 diabetes (ZDF rat).
Engler
Thomas A
TA
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. engler_thomas@lilly.com
Malhotra
Sushant
S
Burkholder
Timothy P
TP
Henry
James R
JR
Mendel
David
D
Porter
Warren J
WJ
Furness
Kelly
K
Diefenbacher
Clive
C
Marquart
Angela
A
Reel
Jon K
JK
Li
Yihong
Y
Clayton
Joshua
J
Cunningham
Brian
B
McLean
Johnathan
J
O'toole
John C
JC
Brozinick
Joseph
J
Hawkins
Eric
E
Misener
Elizabeth
E
Briere
Daniel
D
Brier
Richard A
RA
Wagner
Jill R
JR
Campbell
Robert M
RM
Anderson
Bryan D
BD
Vaughn
Renee
R
Bennett
Donald B
DB
Meier
Timothy I
TI
Cook
James A
JA
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D008301:Maleimides / Q000138:chemical synthesis* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship; D016875:tau Proteins / Q000378:metabolism
D001786:Blood Glucose; D008301:Maleimides; D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3