Synthesis and discovery of macrocyclic polyoxygenated bis-7-azaindolylmaleimides as a novel series of potent and highly selective glycogen synthase kinase-3beta inhibitors.
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.
Kuo
Gee-Hong
GH
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
Prouty
Catherine
C
DeAngelis
Alan
A
Shen
Lan
L
O'Neill
David J
DJ
Shah
Chandra
C
Connolly
Peter J
PJ
Murray
William V
WV
Conway
Bruce R
BR
Cheung
Peter
P
Westover
Lori
L
Xu
Jun Z
JZ
Look
Richard A
RA
Demarest
Keith T
KT
Emanuel
Stuart
S
Middleton
Steven A
SA
Jolliffe
Linda
L
Beavers
Mary Pat
MP
Chen
Xin
X
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
D004791:Enzyme Inhibitors; D004988:Ethers, Cyclic; D007527:Isoenzymes; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D038362:Glycogen Synthase Kinase 3