title: Synthesis and discovery of macrocyclic polyoxygenated bis-7-azaindolylmaleimides as a novel series of potent and highly selective glycogen synthase kinase-3beta inhibitors.
abstract: Attempts to design the macrocyclic maleimides as selective protein kinase C gamma inhibitors led to the unexpected discovery of a novel series of potent and highly selective glycogen synthase kinase-3beta (GSK-3beta) inhibitors. Palladium-catalyzed cross-coupling reactions were used to synthesize the key intermediates 17 and 22 that resulted in the synthesis of novel macrocycles. All three macrocyclic series (bisindolyl-, mixed 7-azaindoleindolyl-, and bis-7-azaindolylmaleimides) were found to have submicromolar inhibitory potency at GSK-3beta with various degrees of selectivity toward other protein kinases. To gain the inhibitory potency at GSK-3beta, the ring sizes of these macrocycles may play a major role. To achieve the selectivity at GSK-3beta, the additional nitrogen atoms in the indole rings may contribute to a significant degree. Overall, the bis-7-azaindolylmaleimides 28 and 29 exhibited little or no inhibitions to a panel of 50 protein kinases. Compound 29 almost behaved as a GSK-3beta specific inhibitor. Both 28 and 29 displayed good potency in GS cell-based assay. Molecular docking studies were conducted in an attempt to rationalize the GSK-3beta selectivity of azaindolylmaleimides.
authors.affiliation: Drug Discovery Division, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Route 202, P.O. Box 300, Raritan, New Jersey 08869, USA. gkuo@prdus.jnj.com
authors.forename: Gee-Hong
authors.initials: GH
authors.lastname: Kuo
authors.forename: Catherine
authors.initials: C
authors.lastname: Prouty
authors.forename: Alan
authors.initials: A
authors.lastname: DeAngelis
authors.forename: Lan
authors.initials: L
authors.lastname: Shen
authors.forename: David J
authors.initials: DJ
authors.lastname: O'Neill
authors.forename: Chandra
authors.initials: C
authors.lastname: Shah
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Connolly
authors.forename: William V
authors.initials: WV
authors.lastname: Murray
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Conway
authors.forename: Peter
authors.initials: P
authors.lastname: Cheung
authors.forename: Lori
authors.initials: L
authors.lastname: Westover
authors.forename: Jun Z
authors.initials: JZ
authors.lastname: Xu
authors.forename: Richard A
authors.initials: RA
authors.lastname: Look
authors.forename: Keith T
authors.initials: KT
authors.lastname: Demarest
authors.forename: Stuart
authors.initials: S
authors.lastname: Emanuel
authors.forename: Steven A
authors.initials: SA
authors.lastname: Middleton
authors.forename: Linda
authors.initials: L
authors.lastname: Jolliffe
authors.forename: Mary Pat
authors.initials: MP
authors.lastname: Beavers
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004988:Ethers, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008301:Maleimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D004988:Ethers, Cyclic; D007527:Isoenzymes; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D038362:Glycogen Synthase Kinase 3