• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

基于结构的新型 II 型 c-Met 抑制剂设计：2. 吡唑酮系列的 SAR 和激酶选择性特征。

Structure-based design of novel class II c-Met inhibitors: 2. SAR and kinase selectivity profiles of the pyrazolone series.

机构信息

Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.

出版信息

J Med Chem. 2012 Mar 8;55(5):1868-97. doi: 10.1021/jm201331s. Epub 2012 Feb 24.

DOI:10.1021/jm201331s
PMID:22320327
Abstract

As part of our effort toward developing an effective therapeutic agent for c-Met-dependent tumors, a pyrazolone-based class II c-Met inhibitor, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1), was identified. Knowledge of the binding mode of this molecule in both c-Met and VEGFR-2 proteins led to a novel strategy for designing more selective analogues of 1. Along with detailed SAR information, we demonstrate that the low kinase selectivity associated with class II c-Met inhibitors can be improved significantly. This work resulted in the discovery of potent c-Met inhibitors with improved selectivity profiles over VEGFR-2 and IGF-1R that could serve as useful tools to probe the relationship between kinase selectivity and in vivo efficacy in tumor xenograft models. Compound 59e (AMG 458) was ultimately advanced into preclinical safety studies.

摘要

作为开发针对 c-Met 依赖性肿瘤的有效治疗剂的努力的一部分，我们发现了一种基于吡唑啉酮的 II 类 c-Met 抑制剂，N-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺（1）。对该分子在 c-Met 和 VEGFR-2 蛋白中的结合模式的了解，为设计更具选择性的 1 类似物提供了新的策略。除了详细的 SAR 信息外，我们还证明了与 II 类 c-Met 抑制剂相关的低激酶选择性可以显著提高。这项工作发现了具有改善的选择性谱的有效 c-Met 抑制剂，相对于 VEGFR-2 和 IGF-1R，其可以作为有用的工具来研究激酶选择性与肿瘤异种移植模型中体内疗效之间的关系。化合物 59e（AMG 458）最终被推进到临床前安全性研究中。

相似文献

1
Structure-based design of novel class II c-Met inhibitors: 2. SAR and kinase selectivity profiles of the pyrazolone series.基于结构的新型 II 型 c-Met 抑制剂设计：2. 吡唑酮系列的 SAR 和激酶选择性特征。
J Med Chem. 2012 Mar 8;55(5):1868-97. doi: 10.1021/jm201331s. Epub 2012 Feb 24.
2
Structure-based design of novel class II c-Met inhibitors: 1. Identification of pyrazolone-based derivatives.基于结构的新型 II 型 c-Met 抑制剂设计：1. 吡唑酮类衍生物的鉴定。
J Med Chem. 2012 Mar 8;55(5):1858-67. doi: 10.1021/jm201330u. Epub 2012 Feb 24.
3
Discovery of a potent, selective, and orally bioavailable c-Met inhibitor: 1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458).一种强效、选择性且口服生物可利用的c-Met抑制剂的发现：1-(2-羟基-2-甲基丙基)-N-(5-(7-甲氧基喹啉-4-基氧基)吡啶-2-基)-5-甲基-3-氧代-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺（AMG 458）。
J Med Chem. 2008 Jul 10;51(13):3688-91. doi: 10.1021/jm800401t. Epub 2008 Jun 14.
4
Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.N-(4-(2-氨基-3-氯吡啶-4-氧基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺（BMS-777607）的发现，一种选择性和口服有效的Met 激酶超家族抑制剂。
J Med Chem. 2009 Mar 12;52(5):1251-4. doi: 10.1021/jm801586s.
5
Design, synthesis and structure-activity relationships of novel biarylamine-based Met kinase inhibitors.新型联苯甲胺基 Met 激酶抑制剂的设计、合成及构效关系研究。
Bioorg Med Chem Lett. 2010 May 1;20(9):2998-3002. doi: 10.1016/j.bmcl.2010.01.042. Epub 2010 Jan 20.
6
Discovery of novel 2-aminopyridine-3-carboxamides as c-Met kinase inhibitors.发现新型 2-氨基吡啶-3-甲酰胺作为 c-Met 激酶抑制剂。
Bioorg Med Chem. 2012 Sep 1;20(17):5169-80. doi: 10.1016/j.bmc.2012.07.007. Epub 2012 Jul 16.
7
Synthesis and structure-activity relationships of pyrazine-pyridine biheteroaryls as novel, potent, and selective vascular endothelial growth factor receptor-2 inhibitors.吡嗪 - 吡啶双杂芳基作为新型、强效和选择性血管内皮生长因子受体 -2 抑制剂的合成及构效关系
J Med Chem. 2005 Jul 28;48(15):4892-909. doi: 10.1021/jm058205b.
8
Design, synthesis and evaluation of highly selective pyridone-based class II MET inhibitors.高选择性吡啶酮类II型MET抑制剂的设计、合成与评价
Bioorg Med Chem Lett. 2014 Aug 1;24(15):3351-5. doi: 10.1016/j.bmcl.2014.05.097. Epub 2014 Jun 6.
9
Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities.基于吡咯并吡啶-吡啶酮的Met激酶抑制剂的发现：合成、X射线晶体学分析及生物活性
J Med Chem. 2008 Sep 11;51(17):5330-41. doi: 10.1021/jm800476q. Epub 2008 Aug 9.
10
Synthesis and c-Met kinase inhibition of 3,5-disubstituted and 3,5,7-trisubstituted quinolines: identification of 3-(4-acetylpiperazin-1-yl)-5-(3-nitrobenzylamino)-7- (trifluoromethyl)quinoline as a novel anticancer agent.3,5-二取代和 3,5,7-三取代喹啉的合成及 c-Met 激酶抑制作用：鉴定出 3-(4-乙酰哌嗪-1-基)-5-(3-硝基苄氨基)-7-(三氟甲基)喹啉为新型抗癌剂。
J Med Chem. 2011 Apr 14;54(7):2127-42. doi: 10.1021/jm101340q. Epub 2011 Mar 15.

引用本文的文献

1
Pharmacophore Modeling of Janus Kinase Inhibitors: Tools for Drug Discovery and Exposition Prediction.Janus激酶抑制剂的药效团模型：药物发现与暴露预测工具
Molecules. 2025 May 16;30(10):2183. doi: 10.3390/molecules30102183.
2
Design, synthesis, and biological evaluation of thiazole/thiadiazole carboxamide scaffold-based derivatives as potential c-Met kinase inhibitors for cancer treatment.基于噻唑/噻二唑甲酰胺骨架的衍生物的设计、合成及生物评价作为潜在的用于癌症治疗的 c-Met 激酶抑制剂。
J Enzyme Inhib Med Chem. 2023 Dec;38(1):2247183. doi: 10.1080/14756366.2023.2247183.
3
Discovery of VEGFR2 inhibitors by integrating naïve Bayesian classification, molecular docking and drug screening approaches.
通过整合朴素贝叶斯分类、分子对接和药物筛选方法发现血管内皮生长因子受体2（VEGFR2）抑制剂
RSC Adv. 2018 Jan 30;8(10):5286-5297. doi: 10.1039/c7ra12259d. eCollection 2018 Jan 29.
4
1,3-diarylpyrazolones as potential anticancer agents for non-small cell lung cancer: Synthesis and antiproliferative activity evaluation.1,3-二芳基吡唑酮类化合物作为潜在的非小细胞肺癌抗癌药物：合成及抗增殖活性评价。
Chem Biol Drug Des. 2022 Apr;99(4):620-633. doi: 10.1111/cbdd.14030. Epub 2022 Mar 1.
5
Modeling and Toxicity Profiling of a Set of Quinoline Derivatives as c-MET Inhibitors in the treatment of Human Tumors.一组喹啉衍生物作为c-MET抑制剂在人类肿瘤治疗中的建模与毒性分析
Turk J Pharm Sci. 2021 Dec 31;18(6):738-743. doi: 10.4274/tjps.galenos.2021.54815.
6
HGF/MET Signaling in Malignant Brain Tumors.HGF/MET 信号在恶性脑肿瘤中的作用。
Int J Mol Sci. 2020 Oct 13;21(20):7546. doi: 10.3390/ijms21207546.
7
Pyrazolone structural motif in medicinal chemistry: Retrospect and prospect.吡唑酮结构母核在药物化学中的研究进展与展望。
Eur J Med Chem. 2020 Jan 15;186:111893. doi: 10.1016/j.ejmech.2019.111893. Epub 2019 Nov 16.
8
Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine Scaffolds.基于异噁唑的 CK1 抑制剂的设计、合成及生物评价：手性吡咯烷骨架的修饰
Molecules. 2019 Mar 1;24(5):873. doi: 10.3390/molecules24050873.
9
Role and Therapeutic Targeting of the HGF/MET Pathway in Glioblastoma.肝细胞生长因子/间质-上皮转化因子通路在胶质母细胞瘤中的作用及治疗靶向
Cancers (Basel). 2017 Jul 11;9(7):87. doi: 10.3390/cancers9070087.
10
Discovery of Potent c-MET Inhibitors with New Scaffold Having Different Quinazoline, Pyridine and Tetrahydro-Pyridothienopyrimidine Headgroups.具有新型骨架的强效c-MET抑制剂的发现，该骨架具有不同的喹唑啉、吡啶和四氢吡啶并噻吩并嘧啶头基。
Molecules. 2016 May 11;21(5):612. doi: 10.3390/molecules21050612.