Synthesis and Discovery of Macrocyclic Polyoxygenated Bis-7-azaindolylmaleimides as a Novel Series of Potent and Highly Selective Glycogen Synthase Kinase-3β Inhibitors

• Published in: Journal of medicinal chemistry 2003-09, Vol.46 (19), p.4021-4031
• Main Authors: Kuo, Gee-Hong, Prouty, Catherine, DeAngelis, Alan, Shen, Lan, O'Neill, David J, Shah, Chandra, Connolly, Peter J, Murray, William V, Conway, Bruce R, Cheung, Peter, Westover, Lori, Xu, Jun Z, Look, Richard A, Demarest, Keith T, Emanuel, Stuart, Middleton, Steven A, Jolliffe, Linda, Beavers, Mary Pat, Chen, Xin
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Medical sciences; Miscellaneous; Pharmacology. Drug treatments
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm030115o

Attempts to design the macrocyclic maleimides as selective protein kinase C γ inhibitors led to the unexpected discovery of a novel series of potent and highly selective glycogen synthase kinase-3β (GSK-3β) 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-3β with various degrees of selectivity toward other protein kinases. To gain the inhibitory potency at GSK-3β, the ring sizes of these macrocycles may play a major role. To achieve the selectivity at GSK-3β, 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-3β 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-3β selectivity of azaindolylmaleimides.