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

Overview

Journal Angew Chem Int Ed Engl

Specialty Chemistry

Date 2016 Jun 30

PMID 27355874

Citations 31

Authors

Steven H Liang

Jinshan Michael Chen

Marc D Normandin

Jeanne S Chang

George C Chang

Christine K Taylor

Patrick Trapa

Mark S Plummer

Kimberly S Para

Edward L Conn

Lori Lopresti-Morrow

Lorraine F Lanyon

James M Cook

Karl E G Richter

Charlie E Nolan

Joel B Schachter

Fouad Janat

Ye Che

Veerabahu Shanmugasundaram

Bruce A Lefker

Bradley E Enerson

Elijahu Livni

Lu Wang

Nicolas J Guehl

Debasis Patnaik

Florence F Wagner

Roy Perlis

Edward B Holson

Stephen J Haggarty

Georges El Fakhri

Ravi G Kurumbail

Neil Vasdev

Affiliations

Soon will be listed here.

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.

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