MK-3328(MK-3328) - 药物靶点：APP_专利_临床

概要

基本信息

药物类型

小分子化药、诊断用放射药物

别名

GEH-200439、MK 3328、[18F]GEH-200439

+ [1]

靶点

APP

作用方式

抑制剂、增强剂

作用机制

APP抑制剂(β-淀粉状蛋白A4抑制剂)、PET imaging(正电子发射断层成像术增强剂)

治疗领域

神经系统疾病其他疾病

在研适应症-

非在研适应症

阿尔茨海默症轻度认知障碍淀粉样蛋白斑

原研机构

Merck Sharp & Dohme Corp.

在研机构-

非在研机构

Merck Sharp & Dohme LLCMerck GmbH

权益机构-

最高研发阶段终止临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C14H9FN4O

InChIKeyWYQHKOHCTMNFAU-UHFFFAOYSA-N

CAS号1201323-97-8

关联

2

项与 MK-3328 相关的临床试验

NCT01385033

/ Terminated临床1期

A Clinical Trial to Characterize the Performance of [18F]MK-3328 in Subjects With Alzheimer's Disease or Mild Cognitive Impairment, and Healthy Young, and Healthy Elderly Subjects

The purpose of this study is to evaluate radiolabeled [18F]MK-3328 as a PET tracer for estimating the regional distribution and extent of amyloid plaques in participants suffering from amnestic mild cognitive impairment (aMCI) and Alzheimer's Disease (AD) versus healthy young and elderly participants. The study hypotheses will test whether [18F]MK-3328 can discriminate between AD participants and cognitively normal elderly control participants as measured by brain regional tracer uptake.

开始日期2011-08-19

申办/合作机构

Merck Sharp & Dohme LLC

NCT00954538

/ Completed临床1期

A Three Part Study to Evaluate the Safety, Radiation Dosimetry, Biokinetics, and Effectiveness of [18F]MK-3328, a Radiotracer for Use in Positron Emission Tomography

This study will estimate the radiochemical and radiation safety and assess the efficacy of [18F]MK-3328, a novel positron emission tomography (PET) tracer. The study safety hypotheses will test whether [18F]MK-3328 is sufficiently safe and well-tolerated, based on an assessment of clinical and laboratory evaluations and adverse experiences in healthy participants, including healthy elderly (HE) participants, and Alzheimer's disease (AD) participants, to permit continued investigation. The study efficacy hypothesis will test whether [18F]MK-3328 can discriminate between AD participants and cognitively normal elderly control participants based on tracer volume of distribution, or one of its surrogates, in brain posterior cingulate gyrus.

开始日期2009-08-01

申办/合作机构

Merck Sharp & Dohme Corp.

100 项与 MK-3328 相关的临床结果

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100 项与 MK-3328 相关的转化医学

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100 项与 MK-3328 相关的专利（医药）

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3

项与 MK-3328 相关的文献（医药）

2020-08-13·Journal of medicinal chemistry1区 · 医学

Imaging Mutant Huntingtin Aggregates: Development of a Potential PET Ligand

1区 · 医学

Article

作者: Giles, Paul ; Gai, Xinjie ; Schaertl, Sabine ; Gadouleau, Elise ; Stepanov, Vladimir ; Nag, Sangram ; Krulle, Thomas ; Orsatti, Laura ; Halldin, Christer ; Thomas, Wayne ; Prime, Michael E. ; Vanräs, Katarina ; Munoz-Sanjuan, Ignacio ; Liu, Longbin ; Nibbio, Martina ; Johnson, Peter D. ; Clark-Frew, Daniel ; Ebneth, Andreas ; Herbst, Todd ; Kiselyov, Alexander ; Monteagudo, Edith ; Hayes, Sarah ; Lee, Matt R. ; Heßmann, Manuela ; Khetarpal, Vinod ; Taylor, Malcolm ; Marston, Richard W. ; Coe, Samuel ; Jia, Zhisheng ; Kotey, Adrian ; Mrzljak, Ladislav ; Miranda-Azpiazu, Patricia ; Vaidya, Darshan ; Brown, Christopher J. ; Svedberg, Marie ; Herrmann, Frank ; Esposito, Simone ; Green, Samantha ; Toth, Miklós ; Sproston, Joanne ; Dominguez, Celia ; Mangette, John E. ; Wigginton, Ian ; Davis, Randall ; Bard, Jonathan A. ; Menta, Sergio ; Mills, Matthew R. ; Scheich, Christoph ; Wityak, John ; Weddell, Derek ; Dickie, Anthony ; Greenaway, Catherine ; Galan, Sebastien ; Takano, Akihiro ; Chen, Xuemei

Mutant huntingtin (mHTT) protein carrying the elongated N-terminal polyglutamine (polyQ) tract misfolds and forms protein aggregates characteristic of Huntington's disease (HD) pathology. A high-affinity ligand specific for mHTT aggregates could serve as a positron emission tomography (PET) imaging biomarker for HD therapeutic development and disease progression. To identify such compounds with binding affinity for polyQ aggregates, we embarked on systematic structural activity studies; lead optimization of aggregate-binding affinity, unbound fractions in brain, permeability, and low efflux culminated in the discovery of compound 1, which exhibited target engagement in autoradiography (ARG) studies in brain slices from HD mouse models and postmortem human HD samples. PET imaging studies with ¹¹C-labeled 1 in both HD mice and WT nonhuman primates (NHPs) demonstrated that the right-hand-side labeled ligand [¹¹C]-1R (CHDI-180R) is a suitable PET tracer for imaging of mHTT aggregates. [¹¹C]-1R is now being advanced to human trials as a first-in-class HD PET radiotracer.

2011-11-01·Nuclear medicine and biology4区 · 医学

[18F]Fluoroazabenzoxazoles as potential amyloid plaque PET tracers: synthesis and in vivo evaluation in rhesus monkey

4区 · 医学

Article

作者: Miller, Patricia ; Hostetler, Eric D. ; Sur, Cyrille ; Gammage, Linda ; Zeng, Zhizhen ; Cook, Jacquelynn J. ; Fan, Hong ; Barrow, James C. ; Harrison, Scott T. ; Wolkenberg, Scott E. ; O'Malley, Stacey ; Sanabria-Bohorquez, Sandra ; Mulhearn, James ; Connolly, Brett ; Williams, David L. Jr. ; Hargreaves, Richard J.

INTRODUCTION:

An (18)F-labeled positron emission tomography (PET) tracer for amyloid plaque is desirable for early diagnosis of Alzheimer's disease, particularly to enable preventative treatment once effective therapeutics are available. Similarly, such a tracer would be useful as a biomarker for enrollment of patients in clinical trials for evaluation of antiamyloid therapeutics. Furthermore, changes in the level of plaque burden as quantified by an amyloid plaque PET tracer may provide valuable insights into the effectiveness of amyloid-targeted therapeutics. This work describes our approach to evaluate and select a candidate PET tracer for in vivo quantification of human amyloid plaque.

METHODS:

Ligands were evaluated for their in vitro binding to human amyloid plaques, lipophilicity and predicted blood-brain barrier permeability. Candidates with favorable in vitro properties were radiolabeled with (18)F and evaluated in vivo. Baseline PET scans in rhesus monkey were conducted to evaluate the regional distribution and kinetics of each tracer using tracer kinetic modeling methods. High binding potential in cerebral white matter and cortical grey matter was considered an unfavorable feature of the candidate tracers.

RESULTS:

[(18)F]MK-3328 showed the most favorable combination of low in vivo binding potential in white matter and cortical grey matter in rhesus monkeys, low lipophilicity (Log D=2.91) and high affinity for human amyloid plaques (IC(50)=10.5±1.3 nM).

CONCLUSIONS:

[(18)F]MK-3328 was identified as a promising PET tracer for in vivo quantification of amyloid plaques, and further evaluation in humans is warranted.

2011-07-14·ACS medicinal chemistry letters3区 · 医学

Synthesis and Evaluation of 5-Fluoro-2-aryloxazolo[5,4-b]pyridines as β-Amyloid PET Ligands and Identification of MK-3328

3区 · 医学

Article

作者: Wolkenberg, Scott E. ; Hartman, George D. ; Sur, Cyrille ; Sanabria-Bohórquez, Sandra ; O’Malley, Stacey S. ; Mulhearn, James ; Culberson, J. Christopher ; Hostetler, Eric D. ; Miller, Patricia J. ; Harrison, Scott T. ; Zeng, Zhizhen ; Fan, Hong ; Williams, David L. ; Cook, Jacquelynn J. ; Barrow, James C. ; Gammage, Linda ; Hargreaves, Richard J.

5-Fluoro-2-aryloxazolo[5,4-b]pyridines were synthesized and investigated as potential (18)F containing β-amyloid PET ligands. In competition binding assays using human AD brain homogenates, compounds 14b, 16b, and 17b were identified as having favorable potency versus human β-amyloid plaque and were radiolabeled for further evaluation in in vitro binding and in vivo PET imaging experiments. These studies led to the identification of 17b (MK-3328) as a candidate PET ligand for the clinical assessment of β-amyloid plaque load.

100 项与 MK-3328 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
轻度认知障碍	临床1期	-	Merck Sharp & Dohme LLC	2011-08-19
淀粉样蛋白斑	临床1期	-	Merck Sharp & Dohme LLC	2011-08-19
阿尔茨海默症	临床1期	-	Merck Sharp & Dohme LLC	2011-08-19

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01385033 (3328-002, CTgov)	临床1期	阿尔茨海默症 \| 淀粉样蛋白斑 \| 轻度认知障碍	20	[18F\]MK-3328	艱衊憲構艱網鏇餘鹹鹽(製願獵齋鬱艱窪夢獵憲) = 獵鏇壓壓簾餘壓廠繭願遞襯艱醖窪鬱繭衊膚鬱 (夢範壓夢積鬱選窪艱膚, 齋獵構製積願網範製築 ~ 鹽糧廠繭壓鑰鏇網願顧) 更多	-	2014-02-20
NCT00954538 (CTgov)	临床1期	阿尔茨海默症	19	[18F\]MK-3328 (All Study Participants)	積窪繭構衊膚鑰淵製襯 = 築顧網簾蓋醖襯膚齋鹽廠襯鏇範壓鹽築壓糧糧 (衊糧蓋顧餘鑰憲蓋蓋餘, 糧廠糧鬱窪憲選衊齋製 ~ 鏇簾簾憲鬱鏇糧繭顧觸) 更多	-	2014-02-05
NCT00954538 (CTgov)	临床1期	阿尔茨海默症	19	[18F\]MK-3328 (Healthy Participants (Part I))	壓憲餘選網鹽獵糧鹹觸(製選蓋顧簾鏇獵壓壓糧) = 鬱鬱獵選淵齋憲簾廠齋艱齋獵憲獵網觸餘繭艱 (簾醖積窪齋網鏇壓顧糧, 2.0) 更多	-	2014-02-05