title: The identification of 8,9-dimethoxy-5-(2-aminoalkoxy-pyridin-3-yl)-benzo[c][2,7]naphthyridin-4-ylamines as potent inhibitors of 3-phosphoinositide-dependent kinase-1 (PDK-1).
abstract: A series of 8,9-dimethoxy-5-(2-aminoalkoxy-pyridin-3-yl)-benzo[c][2,7]naphthyridin-4-ylamine-based inhibitors of 3-phosphoinositide-dependent kinase-1 (PDK-1) has been identified. Several examples appear to be potent and relatively selective inhibitors of PDK-1 over the related AGC kinases PKA, PKB/AKT, and p70S6K. The introduction of a stereochemical center beside the amino substituent on the aminoalkoxy-side chain had little effect upon the inhibitory activity against these enzymes, and X-ray crystallographic analyses of a representative pair of enantiomeric inhibitors bound to the active site of PDK-1 revealed comparable binding modes for each enantiomer.
authors.affiliation: Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. nittoli@hotmail.com
authors.forename: Thomas
authors.initials: T
authors.lastname: Nittoli
authors.forename: Russell G
authors.initials: RG
authors.lastname: Dushin
authors.forename: Charles
authors.initials: C
authors.lastname: Ingalls
authors.forename: Katherine
authors.initials: K
authors.lastname: Cheung
authors.forename: M Brawner
authors.initials: MB
authors.lastname: Floyd
authors.forename: Heidi
authors.initials: H
authors.lastname: Fraser
authors.forename: Andrea
authors.initials: A
authors.lastname: Olland
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Hu
authors.forename: George
authors.initials: G
authors.lastname: Grosu
authors.forename: Xin
authors.initials: X
authors.lastname: Han
authors.forename: Kim
authors.initials: K
authors.lastname: Arndt
authors.forename: Bing
authors.initials: B
authors.lastname: Guo
authors.forename: Allan
authors.initials: A
authors.lastname: Wissner
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D055672:Static Electricity; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011725:Pyridines; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases