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

被引：69

作者：

Liang, Steven H. ^{[1
,2
]}

Chen, Jinshan Michael ^{[3
]}

Normandin, Marc D. ^{[1
,2
]}

Chang, Jeanne S. ^{[3
]}

Chang, George C. ^{[3
]}

Taylor, Christine K. ^{[3
]}

Trapa, Patrick ^{[4
]}

Plummer, Mark S. ^{[3
]}

Para, Kimberly S. ^{[3
]}

Conn, Edward L. ^{[3
]}

Lopresti-Morrow, Lori ^{[3
]}

Lanyon, Lorraine F. ^{[3
]}

Cook, James M. ^{[3
]}

Richter, Karl E. G. ^{[3
]}

Nolan, Charlie E. ^{[3
]}

Schachter, Joel B. ^{[3
]}

Janat, Fouad ^{[3
]}

Che, Ye ^{[3
]}

Shanmugasundaram, Veerabahu ^{[3
]}

Lefker, Bruce A. ^{[4
]}

Enerson, Bradley E. ^{[3
]}

Livni, Elijahu ^{[1
,2
]}

Wang, Lu ^{[1
,2
]}

Guehl, Nicolas J. ^{[1
,2
]}

Patnaik, Debasis ^{[6
,7
]}

Wagner, Florence F. ^{[5
]}

Perlis, Roy ^{[5
,6
,7
]}

Holson, Edward B. ^{[5
]}

Haggarty, Stephen J. ^{[6
,7
]}

El Fakhri, Georges ^{[1
,2
]}

Kurumbail, Ravi G. ^{[3
]}

Vasdev, Neil ^{[1
,2
]}

机构：

[1] Massachusetts Gen Hosp, Gordon Ctr Med Imaging & Nucl Med & Mol Imaging, Boston, MA 02114 USA

[2] Harvard Med Sch, Dept Radiol, Boston, MA 02114 USA

[3] Pfizer Worldwide Res & Dev, Groton Labs, Eastern Point Rd, Groton, CT 06340 USA

[4] Pfizer Worldwide Res & Dev, 610 Main St, Cambridge, MA 02139 USA

[5] Broad Inst, Stanley Ctr Psychiat Res, 415 Main St, Cambridge, MA 02142 USA

[6] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, 185 Cambridge St, Boston, MA 02114 USA

[7] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, 185 Cambridge St, Boston, MA 02114 USA

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2016年 / 55卷 / 33期

关键词：

Alzheimer's disease; glycogen synthase kinase-3; phosphorylation; positron emission tomography; tau proteins; ALZHEIMERS-DISEASE; TRANSGENIC MICE; GSK-3-BETA; RADIOSYNTHESIS; RADIOTRACER; VIVO;

D O I：

10.1002/anie.201603797

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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 PF367) 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 C-11-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.

引用

页码：9601 / 9605

页数：5

共 41 条

[1] Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase-3 Inhibitors [J].

Luo, Guanglin ;

Chen, Ling ;

Burton, Catherine R. ;

Xiao, Hong ;

Sivaprakasam, Prasanna ;

Krause, Carol M. ;

Cao, Yang ;

Liu, Nengyin ;

Lippy, Jonathan ;

Clarke, Wendy J. ;

Snow, Kimberly ;

Raybon, Joseph ;

Arora, Vinod ;

Pokross, Matt ;

Kish, Kevin ;

Lewis, Hal A. ;

Langley, David R. ;

Macor, John E. ;

Dubowchik, Gene M. .

JOURNAL OF MEDICINAL CHEMISTRY, 2016, 59 (03) :1041-1051

[2] Tau phosphorylation in transgenic mice expressing glycogen synthase kinase-3 beta transgenes [J].

Brownlees, J ;

Irving, NG ;

Brion, JP ;

Gibb, BJM ;

Wagner, U ;

Woodgett, J ;

Miller, CCJ .

NEUROREPORT, 1997, 8 (15) :3251-3255

[3] Glycogen Synthase Kinase-3β2 Has Lower Phosphorylation Activity to Tau than Glycogen Synthase Kinase-3β1 [J].

Saeki, Kazunori ;

Machida, Mayumi ;

Kinoshita, Yutaro ;

Takasawa, Ryoko ;

Tanuma, Sei-ichi .

BIOLOGICAL & PHARMACEUTICAL BULLETIN, 2011, 34 (01) :146-149

[4] Identification of a novel selective and potent inhibitor of glycogen synthase kinase-3 [J].

Noori, Mahboubeh S. ;

Bhatt, Pooja M. ;

Courreges, Maria C. ;

Ghazanfari, Davoud ;

Cuckler, Chaz ;

Orac, Crina M. ;

McMills, Mark C. ;

Schwartz, Frank L. ;

Deosarkar, Sudhir P. ;

Bergmeier, Stephen C. ;

McCall, Kelly D. ;

Goetz, Douglas J. .

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2019, 317 (06) :C1289-C1303

[5] Glycogen synthase kinase-3β-mediated tau phosphorylation in cultured cell lines [J].

Lee, CWC ;

Lau, KF ;

Miller, CCJ ;

Shaw, PC .

NEUROREPORT, 2003, 14 (02) :257-260

[6] Selective loss of glycogen synthase kinase-3α in birds reveals distinct roles for GSK-3 isozymes in tau phosphorylation [J].

Alon, Lina Tsaadon ;

Pietrokovski, Shmuel ;

Barkan, Shay ;

Avrahami, Limor ;

Kaidanovich-Beilin, Oksana ;

Woodgett, James R. ;

Barnea, Anat ;

Eldar-Finkelman, Hagit .

FEBS LETTERS, 2011, 585 (08) :1158-1162

[7] Tau phosphorylation by glycogen synthase kinase 3β modulates enzyme acetylcholinesterase expression [J].

Cortes-Gomez, Maria-Angeles ;

Llorens-Alvarez, Esther ;

Alom, Jordi ;

del Ser, Teodoro ;

Avila, Jesus ;

Saez-Valero, Javier ;

Garcia-Ayllon, Maria-Salud .

JOURNAL OF NEUROCHEMISTRY, 2021, 157 (06) :2091-2105

[8] Exposure to Pyrithiamine Increases β-Amyloid Accumulation, Tau Hyperphosphorylation, and Glycogen Synthase Kinase-3 Activity in the Brain [J].

Zhao, Jing ;

Sun, Xiaojing ;

Yu, Zhe ;

Pan, Xiaoli ;

Gu, Fenghua ;

Chen, Jia ;

Dong, Wenxin ;

Zhao, Lei ;

Zhong, Chunjiu .

NEUROTOXICITY RESEARCH, 2011, 19 (04) :575-583

[9] Leptin inhibits glycogen synthase kinase-3β to prevent tau phosphorylation in neuronal cells [J].

Greco, Steven J. ;

Sarkar, Sraboni ;

Casadesus, Gemma ;

Zhu, Xiongwei ;

Smith, Mark A. ;

Ashford, J. Wesson ;

Johnston, Jane M. ;

Tezapsidis, Nikolaos .

NEUROSCIENCE LETTERS, 2009, 455 (03) :191-194

[10] Glycogen Synthase Kinase-3 Regulates Production of Amyloid-β Peptides and Tau Phosphorylation in Diabetic Rat Brain [J].

Qu, Zhong-Sen ;

Li, Liang ;

Sun, Xiao-Jiang ;

Zhao, Yu-Wu ;

Zhang, Jin ;

Geng, Zhi ;

Fu, Jian-Liang ;

Ren, Qing-Guo .

SCIENTIFIC WORLD JOURNAL, 2014,

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