title: Novel bis(indolyl)maleimide pyridinophanes that are potent, selective inhibitors of glycogen synthase kinase-3.
abstract: Novel bis(indolyl)maleimide pyridinophanes 3, 9a, 9b, 10a, 10b, and 11 were prepared by cobalt-mediated [2+2+2] cycloaddition of an appropriate alpha,omega-diyne with an N,N-dialkylcyanamide. These macrocyclic heterophanes were found to be potent, selective inhibitors of glycogen synthase kinase-3beta. An X-ray structure of a co-crystal of GSK-3beta and 3 (IC(50)=3nM) depicts the hydrogen bonding and hydrophobic interactions in the ATP-binding pocket of this serine/threonine protein kinase.
authors.affiliation: Vascular Research Team, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776, USA. hzhang@prdus.jnj.com
authors.forename: Han-Cheng
authors.initials: HC
authors.lastname: Zhang
authors.forename: Llorente V R
authors.initials: LV
authors.lastname: Boñaga
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.forename: Claudia K
authors.initials: CK
authors.lastname: Derian
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Damiano
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000071679:Glycogen Synthase Kinase 3 beta; D057927:Hydrophobic and Hydrophilic Interactions; D008301:Maleimides / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D008301:Maleimides; D011725:Pyridines; C043592:maleimide; D000255:Adenosine Triphosphate; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3