TY - JOUR
T1 - Structure-based optimization of oxadiazole-based GSK-3 inhibitors
AU - Lo Monte, Fabio
AU - Kramer, Thomas
AU - Gu, Jiamin
AU - Brodrecht, Martin
AU - Pilakowski, Johannes
AU - Fuertes, Ana
AU - Dominguez, Juan Manuel
AU - Plotkin, Batya
AU - Eldar-Finkelman, Hagit
AU - Schmidt, Boris
N1 - Funding Information:
This work was supported by a collaborative project financed by the 7th Framework Program of the European Union: NeuroGSK3.
PY - 2013/3
Y1 - 2013/3
N2 - 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 IC 50 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.
AB - 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 IC 50 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.
KW - Alzheimer's disease
KW - Glycogen synthase Kinase-3 (GSK-3)
KW - Reversible inhibition
KW - Structure-activity relationship (SAR)
KW - Zebrafish phenotype
UR - http://www.scopus.com/inward/record.url?scp=84874943660&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2012.06.006
DO - 10.1016/j.ejmech.2012.06.006
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
AN - SCOPUS:84874943660
SN - 0223-5234
VL - 61
SP - 26
EP - 40
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -