Unknown

Dataset Information

0

Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging.

ABSTRACT: Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncology, and neurology. N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in?vitro and in?vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A (11) C-isotopologue of PF-367 was synthesized and preliminary PET imaging studies in non-human primates confirmed that we have overcome the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding.

SUBMITTER: Liang SH 

PROVIDER: S-EPMC4983481 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging.

Liang Steven H SH   Chen Jinshan Michael JM   Normandin Marc D MD   Chang Jeanne S JS   Chang George C GC   Taylor Christine K CK   Trapa Patrick P   Plummer Mark S MS   Para Kimberly S KS   Conn Edward L EL   Lopresti-Morrow Lori L   Lanyon Lorraine F LF   Cook James M JM   Richter Karl E G KE   Nolan Charlie E CE   Schachter Joel B JB   Janat Fouad F   Che Ye Y   Shanmugasundaram Veerabahu V   Lefker Bruce A BA   Enerson Bradley E BE   Livni Elijahu E   Wang Lu L   Guehl Nicolas J NJ   Patnaik Debasis D   Wagner Florence F FF   Perlis Roy R   Holson Edward B EB   Haggarty Stephen J SJ   El Fakhri Georges G   Kurumbail Ravi G RG   Vasdev Neil N  

Angewandte Chemie (International ed. in English) 20160629 33

Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncology, and neurology. N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an  ...[more]

Similar Datasets

Unknown Tau phosphorylation by glycogen synthase kinase 3β modulates enzyme acetylcholinesterase expression.
| S-EPMC8359467 | biostudies-literature
Unknown Leptin inhibits glycogen synthase kinase-3beta to prevent tau phosphorylation in neuronal cells.
| S-EPMC2681253 | biostudies-literature
Unknown Sulfhydration of AKT triggers Tau-phosphorylation by activating glycogen synthase kinase 3β in Alzheimer's disease.
| S-EPMC7049105 | biostudies-literature
Unknown Stimulation of EphB2 attenuates tau phosphorylation through PI3K/Akt-mediated inactivation of glycogen synthase kinase-3?.
| S-EPMC4484244 | biostudies-literature
Unknown Isoform-selective decrease of glycogen synthase kinase-3-beta (GSK-3β) reduces synaptic tau phosphorylation, transcellular spreading, and aggregation.
| S-EPMC7848608 | biostudies-literature
Unknown Phosphorylation of tau by glycogen synthase kinase 3beta affects the ability of tau to promote microtubule self-assembly.
| S-EPMC1218378 | biostudies-other
Unknown Acute Glycogen Synthase Kinase-3 Inhibition Modulates Human Cardiac Conduction.
| S-EPMC9626903 | biostudies-literature
Unknown Discovery and Development of Small-Molecule Inhibitors of Glycogen Synthase.
| S-EPMC7233370 | biostudies-literature
Unknown AMP-activated protein kinase modulates tau phosphorylation and tau pathology in vivo.
| S-EPMC4882625 | biostudies-literature
Unknown Glycogen synthase kinase-3 regulates production of amyloid-β peptides and tau phosphorylation in diabetic rat brain.
| S-EPMC3997149 | biostudies-other