2. Academic Validation
  3. Synthesis and discovery of macrocyclic polyoxygenated bis-7-azaindolylmaleimides as a novel series of potent and highly selective glycogen synthase kinase-3beta inhibitors

Synthesis and discovery of macrocyclic polyoxygenated bis-7-azaindolylmaleimides as a novel series of potent and highly selective glycogen synthase kinase-3beta inhibitors

  • J Med Chem. 2003 Sep 11;46(19):4021-31. doi: 10.1021/jm030115o.
Gee-Hong Kuo 1,  Catherine Prouty,  Alan DeAngelis,  Lan Shen,  David J O'Neill,  Chandra Shah,  Peter J Connolly,  William V Murray,  Bruce R Conway,  Peter Cheung,  Lori Westover,  Jun Z Xu,  Richard A Look,  Keith T Demarest,  Stuart Emanuel,  Steven A Middleton,  Linda Jolliffe,  Mary Pat Beavers,  Xin Chen
Affiliations

Affiliation

  • 1 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
PMID: 12954055 DOI: 10.1021/jm030115o
Abstract

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.

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