Substituted 3-imidazo[1,2-a]pyridin-3-yl- 4-(1,2,3,4-tetrahydro-[1,4]diazepino-[6,7,1-hi]indol-7-yl)pyrrole-2,5-diones as highly selective and potent inhibitors of glycogen synthase kinase-3.
Glycogen synthase kinase-3 (GSK3) is involved in signaling from the insulin receptor. Inhibitors of GSK3 are expected to effect lowering of plasma glucose similar to insulin, making GSK3 an attractive target for the treatment of type 2 diabetes. Herein we report the discovery of a series of potent and selective GSK3 inhibitors. Compounds 7-12 show oral activity in an in vivo model of type II diabetes, and 9 and 12 have desirable PK properties.
Engler
Thomas A
TA
Lilly Research Laboratories, A Division of Eli Lilly & Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. Engler_Thomas@lilly.com
Henry
James R
JR
Malhotra
Sushant
S
Cunningham
Brian
B
Furness
Kelly
K
Brozinick
Joseph
J
Burkholder
Timothy P
TP
Clay
Michael P
MP
Clayton
Joshua
J
Diefenbacher
Clive
C
Hawkins
Eric
E
Iversen
Philip W
PW
Li
Yihong
Y
Lindstrom
Terry D
TD
Marquart
Angela L
AL
McLean
Johnathan
J
Mendel
David
D
Misener
Elizabeth
E
Briere
Daniel
D
O'Toole
John C
JC
Porter
Warren J
WJ
Queener
Steven
S
Reel
Jon K
JK
Owens
Rebecca A
RA
Brier
Richard A
RA
Eessalu
Thomas E
TE
Wagner
Jill R
JR
Campbell
Robert M
RM
Vaughn
Renee
R
D000284:Administration, Oral; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker
D007093:Imidazoles; D011725:Pyridines; D011758:Pyrroles; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3