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A novel series of 6-aryl-pyrazolo[3,4-b]pyridines has been identified that are potent inhibitors of glycogen synthase kinase-3 (GSK-3).

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Fused pyridine derivativesFused pyridine derivatives R 0450 6-Aryl-pyrazolo[3,4-b]pyridines: Potent Inhibitors of Glycogen Synthase Kinase-3 (GSK-3). -Due to a hydrogen bond between the N-6 position of previously synthesized potent pyrazolopyridazine-based inhibitors of GSK-3 and a water lattice, it is suggested to displace the structural waters from the binding site via insertion of a suitably functionalized group at the 6-position of the pyrazolopyridine nucleus. This hypothesis is tested by the design and synthesis of functionalized 6-aryl pyridines like (VIII). Moreover, not only the structure-activity relationship around the C-6 position of the pyrazolopyridine nucleus is investigated but also the C-5 position. Insertion of bromine at C-5 affords an additional improvement in potency. -(WITHERINGTON*, J.; BORDAS, V.; GAIBA, A.; GARTON, N. S.; NAYLOR, A.; RAWLINGS, A. D.; SLINGSBY, B. P.; SMITH, D. G.; TAKLE, A. K.; WARD, R. W.; Bioorg. Med. Chem. Lett. 13 (2003) 18, 3055-3057; Dep. Med. Chem., SmithKline Beecham Pharm.,

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