title: Structure-based optimization of oxadiazole-based GSK-3 inhibitors.
abstract: Inhibition of glycogen synthase kinase-3 (GSK-3) induces neuroprotective effects, e.g. decreases β-amyloid production and reduces tau hyperphosphorylation, which are both associated with Alzheimer's disease (AD). The two isoforms of GSK-3 in mammalians are GSK-3α and β, which share 98% homology in their catalytic domains. We investigated GSK-3 inhibitors based on 2 different scaffolds in order to elucidate the demands of the ATP-binding pocket [1]. Particularly, the oxadiazole scaffold provided potent and selective GSK-3 inhibitors. For example, the most potent inhibitor of the present series, the acetamide 26d, is characterized by an IC50 of 2 nM for GSK-3α and 17 nM for GSK-3β. In addition, the benzodioxane 8g showed up to 27-fold selectivity for GSK-3α over GSK-3β, with an IC50 of 35 nM for GSK-3α. Two GSK-3 inhibitors were further profiled for efficacy and toxicity in the wild-type (wt) zebrafish embryo assay to evaluate simultaneously permeability and safety.
authors: Clemens Schöpf - Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Petersenstrasse 22, 64287 Darmstadt, Germany. Fabio.Lo-Monte@gmx.de
authors: Fabio
authors: F
authors: Lo Monte
authors: Thomas
authors: T
authors: Kramer
authors: Jiamin
authors: J
authors: Gu
authors: Martin
authors: M
authors: Brodrecht
authors: Johannes
authors: J
authors: Pilakowski
authors: Ana
authors: A
authors: Fuertes
authors: Juan Manuel
authors: JM
authors: Dominguez
authors: Batya
authors: B
authors: Plotkin
authors: Hagit
authors: H
authors: Eldar-Finkelman
authors: Boris
authors: B
authors: Schmidt
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015027:Zebrafish
chemical_list: D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D038362:Glycogen Synthase Kinase 3