Peat Andrew J, Garrido Dulce, Boucheron Joyce A, Schweiker Stephanie L, Dickerson Scott H, Wilson Jayme R, Wang Tony Y, Thomson Stephen A
GlaxoSmithKline Research and Development, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
Bioorg Med Chem Lett. 2004 May 3;14(9):2127-30. doi: 10.1016/j.bmcl.2004.02.037.
A novel series of [1-(1H-benzimidazol-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl] arylhydrazones was synthesized and shown to potently inhibit glycogen synthase kinase-3 (GSK-3). In light of detailed structure-activity relationships and structural knowledge of the GSK-3 binding pocket, a benzimidazole substituent was incorporated onto the pyrazolopyrimidine core resulting in improved potency over previous analogs. More importantly, these derivatives show low nanomolar efficacy for stimulating glycogen synthesis in vitro and therefore may be useful in the treatment of type 2 diabetes mellitus.
