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).
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.
Nittoli
Thomas
T
Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. nittoli@hotmail.com
Dushin
Russell G
RG
Ingalls
Charles
C
Cheung
Katherine
K
Floyd
M Brawner
MB
Fraser
Heidi
H
Olland
Andrea
A
Hu
Yongbo
Y
Grosu
George
G
Han
Xin
X
Arndt
Kim
K
Guo
Bing
B
Wissner
Allan
A
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
D047428:Protein Kinase Inhibitors; D011725:Pyridines; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases