Structural Basis for Achieving GSK-3β Inhibition with High Potency, Selectivity, and Brain Exposure for Positron Emission Tomography Imaging and Drug Discovery.,Journal of Medicinal Chemistry

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Structural Basis for Achieving GSK-3β Inhibition with High Potency, Selectivity, and Brain Exposure for Positron Emission Tomography Imaging and Drug Discovery.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-10-21 , DOI: 10.1021/acs.jmedchem.9b01030
Vadim Bernard-Gauthier _{1,

2,

3} , Andrew V Mossine ₄ , Ashley Knight _{1,

2,

5} , Debasis Patnaik ₆ , Wen-Ning Zhao ₆ , Chialin Cheng ₆ , Hema S Krishnan ₃ , Lucius L Xuan ₆ , Peter S Chindavong ₆ , Surya A Reis ₆ , Jinshan Michael Chen ₇ , Xia Shao ₄ , Jenelle Stauff ₄ , Janna Arteaga ₄ , Phillip Sherman ₄ , Nicolas Salem ₈ , David Bonsall ₉ , Brenda Amaral ₈ , Cassis Varlow ₁ , Lisa Wells ₉ , Laurent Martarello ₈ , Shil Patel ₅ , Steven H Liang ₃ , Ravi G Kurumbail ₇ , Stephen J Haggarty ₆ , Peter J H Scott _{4,

10} , Neil Vasdev _{1,

2,

3}

Affiliation

Azrieli Centre for Neuro-Radiochemistry, Research Imaging Centre , Centre for Addiction and Mental Health , Toronto , Ontario M5T 1R8 , Canada.
Department of Psychiatry/Institute of Medical Science , University of Toronto , Toronto , Ontario M5T 1R8 , Canada.
Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology , Harvard Medical School , Boston , Massachusetts 02114 , United States.
Division of Nuclear Medicine, Department of Radiology , The University of Michigan Medical School , Ann Arbor , Michigan 48109 , United States.
Eisai AiM Institute , Boston , Massachusetts 01810 , United States.
Chemical Neurobiology Laboratory, Massachusetts General Hospital, Center for Genomic Medicine, Departments of Neurology & Psychiatry , Harvard Medical School , Boston , Massachusetts 02114 , United States.
Pfizer Worldwide Research and Development , Groton Laboratories , Eastern Point Road , Groton , Connecticut 06340 , United States.
Biogen, Research and Early Development Imaging , Cambridge , Massachusetts 02142 , United States.
Invicro , London W12 0NN , U.K.
The Interdepartmental Program in Medicinal Chemistry , University of Michigan , Ann Arbor , Michigan 48109 , United States.

Using structure-guided design, several cell based assays, and microdosed positron emission tomography (PET) imaging, we identified a series of highly potent, selective, and brain-penetrant oxazole-4-carboxamide-based inhibitors of glycogen synthase kinase-3 (GSK-3). An isotopologue of our first-generation lead, [³H]PF-367, demonstrates selective and specific target engagement in vitro, irrespective of the activation state. We discovered substantial ubiquitous GSK-3-specific radioligand binding in Tg2576 Alzheimer’s disease (AD), suggesting application for these compounds in AD diagnosis and identified [¹¹C]OCM-44 as our lead GSK-3 radiotracer, with optimized brain uptake by PET imaging in nonhuman primates. GSK-3β-isozyme selectivity was assessed to reveal OCM-51, the most potent (IC₅₀ = 0.030 nM) and selective (>10-fold GSK-3β/GSK-3α) GSK-3β inhibitor known to date. Inhibition of CRMP2^T514 and tau phosphorylation, as well as favorable therapeutic window against WNT/β-catenin signaling activation, was observed in cells.

中文翻译：

以高效力、选择性和脑暴露实现正电子发射断层扫描成像和药物发现的 GSK-3β 抑制的结构基础。

使用结构引导设计、多种基于细胞的测定和微剂量正电子发射断层扫描 (PET) 成像，我们鉴定了一系列高效、选择性和脑渗透性基于恶唑-4-甲酰胺的糖原合酶激酶 3 抑制剂。葛兰素史克-3）。我们的第一代先导化合物 [ ³ H]PF-367 的同位素体在体外表现出选择性和特异性的靶标参与，而与激活状态无关。我们在 Tg2576 阿尔茨海默病 (AD) 中发现了大量普遍存在的 GSK-3 特异性放射性配体结合，建议这些化合物在 AD 诊断中的应用，并确定 [ ¹¹ C]OCM-44 作为我们的主要 GSK-3 放射性示踪剂，并通过 PET 优化大脑摄取非人类灵长类动物的成像。评估 GSK-3β-同工酶选择性以揭示 OCM-51，这是迄今为止已知的最有效（IC ₅₀ = 0.030 nM）和选择性（>10 倍 GSK-3β/GSK-3α）GSK-3β 抑制剂。在细胞中观察到 CRMP2 ^T514和 tau 磷酸化的抑制，以及针对 WNT/β-连环蛋白信号激活的有利治疗窗口。

更新日期：2019-10-21

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