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：66

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 40 条

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