title: 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.
abstract: 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.
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. Engler_Thomas@lilly.com
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Engler
authors.forename: James R
authors.initials: JR
authors.lastname: Henry
authors.forename: Sushant
authors.initials: S
authors.lastname: Malhotra
authors.forename: Brian
authors.initials: B
authors.lastname: Cunningham
authors.forename: Kelly
authors.initials: K
authors.lastname: Furness
authors.forename: Joseph
authors.initials: J
authors.lastname: Brozinick
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Burkholder
authors.forename: Michael P
authors.initials: MP
authors.lastname: Clay
authors.forename: Joshua
authors.initials: J
authors.lastname: Clayton
authors.forename: Clive
authors.initials: C
authors.lastname: Diefenbacher
authors.forename: Eric
authors.initials: E
authors.lastname: Hawkins
authors.forename: Philip W
authors.initials: PW
authors.lastname: Iversen
authors.forename: Yihong
authors.initials: Y
authors.lastname: Li
authors.forename: Terry D
authors.initials: TD
authors.lastname: Lindstrom
authors.forename: Angela L
authors.initials: AL
authors.lastname: Marquart
authors.forename: Johnathan
authors.initials: J
authors.lastname: McLean
authors.forename: David
authors.initials: D
authors.lastname: Mendel
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Misener
authors.forename: Daniel
authors.initials: D
authors.lastname: Briere
authors.forename: John C
authors.initials: JC
authors.lastname: O'Toole
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Porter
authors.forename: Steven
authors.initials: S
authors.lastname: Queener
authors.forename: Jon K
authors.initials: JK
authors.lastname: Reel
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Owens
authors.forename: Richard A
authors.initials: RA
authors.lastname: Brier
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Eessalu
authors.forename: Jill R
authors.initials: JR
authors.lastname: Wagner
authors.forename: Robert M
authors.initials: RM
authors.lastname: Campbell
authors.forename: Renee
authors.initials: R
authors.lastname: Vaughn
mesh_terms: 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
chemical_list: D007093:Imidazoles; D011725:Pyridines; D011758:Pyrroles; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3