title: The development of potent and selective bisarylmaleimide GSK3 inhibitors.
abstract: 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).
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. engler_thomas@lilly.com
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Engler
authors.forename: Sushant
authors.initials: S
authors.lastname: Malhotra
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Burkholder
authors.forename: James R
authors.initials: JR
authors.lastname: Henry
authors.forename: David
authors.initials: D
authors.lastname: Mendel
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Porter
authors.forename: Kelly
authors.initials: K
authors.lastname: Furness
authors.forename: Clive
authors.initials: C
authors.lastname: Diefenbacher
authors.forename: Angela
authors.initials: A
authors.lastname: Marquart
authors.forename: Jon K
authors.initials: JK
authors.lastname: Reel
authors.forename: Yihong
authors.initials: Y
authors.lastname: Li
authors.forename: Joshua
authors.initials: J
authors.lastname: Clayton
authors.forename: Brian
authors.initials: B
authors.lastname: Cunningham
authors.forename: Johnathan
authors.initials: J
authors.lastname: McLean
authors.forename: John C
authors.initials: JC
authors.lastname: O'toole
authors.forename: Joseph
authors.initials: J
authors.lastname: Brozinick
authors.forename: Eric
authors.initials: E
authors.lastname: Hawkins
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Misener
authors.forename: Daniel
authors.initials: D
authors.lastname: Briere
authors.forename: Richard A
authors.initials: RA
authors.lastname: Brier
authors.forename: Jill R
authors.initials: JR
authors.lastname: Wagner
authors.forename: Robert M
authors.initials: RM
authors.lastname: Campbell
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Anderson
authors.forename: Renee
authors.initials: R
authors.lastname: Vaughn
authors.forename: Donald B
authors.initials: DB
authors.lastname: Bennett
authors.forename: Timothy I
authors.initials: TI
authors.lastname: Meier
authors.forename: James A
authors.initials: JA
authors.lastname: Cook
mesh_terms: 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
chemical_list: D001786:Blood Glucose; D008301:Maleimides; D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3