title: Design, synthesis, and biological evaluation of novel 7-azaindolyl-heteroaryl-maleimides as potent and selective glycogen synthase kinase-3beta (GSK-3beta) inhibitors.
abstract: Two approaches were developed to synthesize the novel 7-azaindolyl-heteroarylmaleimides. The first approach was based upon the palladium-catalyzed Suzuki cross-coupling or Stille cross-coupling of 2-chloro-maleimide 5 with various arylboronic acids or arylstannanes. The second approach was based upon the condensation of ethyl 7-azaindolyl-3-glyoxylate 12 with various acetamides. The hydroxypropyl-substituted 7-azaindolylmaleimide template was first used to screen different heteroaryls attached to the maleimide. Replacement of hydroxypropyl with different chain lengths and different functional groups were studied next. Many compounds synthesized were demonstrated to have high potency at GSK-3beta, good GS activity in HEK293 cells and good to excellent metabolic stability in human liver microsomes. Three representative compounds (21, 33, and 34) were demonstrated to have good selectivity against a panel of 80 kinase assays. Among them, compound 33 exhibited very weak inhibitions at the other 79 kinase assays, and behaved as a highly selective GSK-3beta inhibitor.
authors.affiliation: Drug Discovery Division, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., Raritan, NJ 08869-0602, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: O'Neill
authors.forename: Lan
authors.initials: L
authors.lastname: Shen
authors.forename: Catherine
authors.initials: C
authors.lastname: Prouty
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Conway
authors.forename: Lori
authors.initials: L
authors.lastname: Westover
authors.forename: Jun Z
authors.initials: JZ
authors.lastname: Xu
authors.forename: Han-Cheng
authors.initials: HC
authors.lastname: Zhang
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
authors.forename: William V
authors.initials: WV
authors.lastname: Murray
authors.forename: Keith T
authors.initials: KT
authors.lastname: Demarest
authors.forename: Gee-Hong
authors.initials: GH
authors.lastname: Kuo
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008301:Maleimides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D011817:Rabbits; D013379:Substrate Specificity
chemical_list: D001372:Aza Compounds; D004791:Enzyme Inhibitors; D008301:Maleimides; C043592:maleimide; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3