• 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

新型 6-((1 H-吡唑并[4,3- b]吡啶-3-基)氨基)苯并[ d]异噻唑-3-甲酰胺类代谢型谷氨酸受体 4(mGlu4)正变构调节剂的发现、构效关系及生物学特性研究。

Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu).

机构信息

Vanderbilt Center for Neuroscience Drug Discovery , Vanderbilt University , Nashville , Tennessee 37232 , United States.

Department of Pharmacology , Vanderbilt University , Nashville , Tennessee 37232 , United States.

出版信息

J Med Chem. 2019 Jan 10;62(1):342-358. doi: 10.1021/acs.jmedchem.8b00994. Epub 2018 Oct 10.

DOI:10.1021/acs.jmedchem.8b00994
PMID:30247901
Abstract

This work describes the discovery and characterization of novel 6-(1 H-pyrazolo[4,3- b]pyridin-3-yl)amino-benzo[ d]isothiazole-3-carboxamides as mGlu PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previously discovered mGlu PAMs. From this work, 27o (VU6001376) was identified as a potent (EC = 50.1 nM, 50.5% GluMax) and selective mGlu PAM with an excellent rat DMPK profile ( in vivo rat CL = 3.1 mL/min/kg, t = 445 min, CYP1A2 IC > 30 μM). Compound 27o was also active in reversing haloperidol induced catalepsy in a rodent preclinical model of Parkinson's disease.

摘要

本工作描述了新型 6-(1H-吡唑并[4,3-b]哒嗪-3-基)氨基-苯并[d]异噻唑-3-甲酰胺类作为 mGlu PAMs 的发现和特征。与先前发现的 mGlu PAMs 相比，该支架提供了改善的代谢清除率和 CYP1A2 谱。由此，27o（VU6001376）被鉴定为一种有效的（EC = 50.1 nM，50.5% GluMax）和选择性的 mGlu PAM，具有出色的大鼠 DMPK 特征（体内大鼠 CL = 3.1 mL/min/kg，t = 445 min，CYP1A2 IC > 30 μM）。化合物 27o 在一种帕金森病啮齿动物临床前模型中也能有效逆转氟哌啶醇诱导的僵住症。

相似文献

1
Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu).新型 6-((1 H-吡唑并[4,3- b]吡啶-3-基)氨基)苯并[ d]异噻唑-3-甲酰胺类代谢型谷氨酸受体 4(mGlu4)正变构调节剂的发现、构效关系及生物学特性研究。
J Med Chem. 2019 Jan 10;62(1):342-358. doi: 10.1021/acs.jmedchem.8b00994. Epub 2018 Oct 10.
2
Development and Antiparkinsonian Activity of VU0418506, a Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor 4 Homomers without Activity at mGlu2/4 Heteromers.代谢型谷氨酸受体4同聚体的选择性正变构调节剂VU0418506的研发及其抗帕金森病活性：VU0418506对代谢型谷氨酸受体2/4异聚体无活性
ACS Chem Neurosci. 2016 Sep 21;7(9):1201-11. doi: 10.1021/acschemneuro.6b00036. Epub 2016 Aug 5.
3
Discovery, Synthesis, and Preclinical Characterization of N-(3-Chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506), a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4).代谢型谷氨酸受体4（mGlu4）新型正变构调节剂N-（3-氯-4-氟苯基）-1H-吡唑并[4,3-b]吡啶-3-胺（VU0418506）的发现、合成及临床前特性研究
ACS Chem Neurosci. 2016 Sep 21;7(9):1192-200. doi: 10.1021/acschemneuro.6b00035. Epub 2016 May 3.
4
Discovery and characterization of N-(1,3-dialkyl-1H-indazol-6-yl)-1H-pyrazolo[4,3-b]pyridin-3-amine scaffold as mGlu positive allosteric modulators that mitigate CYP1A2 induction liability.发现并表征N-(1,3-二烷基-1H-吲唑-6-基)-1H-吡唑并[4,3-b]吡啶-3-胺骨架作为可减轻CYP1A2诱导风险的代谢型谷氨酸受体正向变构调节剂。
Bioorg Med Chem Lett. 2018 Aug 15;28(15):2641-2646. doi: 10.1016/j.bmcl.2018.06.034. Epub 2018 Jun 19.
5
Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy.发现3-氨基吡啶甲酰胺作为代谢型谷氨酸受体亚型4（mGlu4）的正变构调节剂弹头，可实现中枢神经系统暴露及体内疗效。
Bioorg Med Chem Lett. 2016 Jun 15;26(12):2915-2919. doi: 10.1016/j.bmcl.2016.04.041. Epub 2016 Apr 19.
6
Discovery and optimization of a novel CNS penetrant series of mGlu PAMs based on a 1,4-thiazepane core with in vivo efficacy in a preclinical Parkinsonian model.基于 1,4-噻唑烷核心发现并优化新型 CNS 穿透性 mGlu PAMs 系列化合物，在临床前帕金森模型中具有体内疗效。
Bioorg Med Chem Lett. 2021 Apr 1;37:127838. doi: 10.1016/j.bmcl.2021.127838. Epub 2021 Feb 5.
7
An orally bioavailable positive allosteric modulator of the mGlu4 receptor with efficacy in an animal model of motor dysfunction.一种具有口服生物利用度的 mGlu4 受体正变构调节剂，在运动功能障碍动物模型中具有疗效。
Bioorg Med Chem Lett. 2010 Aug 15;20(16):4901-5. doi: 10.1016/j.bmcl.2010.06.078. Epub 2010 Jun 25.
8
Discovery of Novel Central Nervous System Penetrant Metabotropic Glutamate Receptor Subtype 2 (mGlu) Negative Allosteric Modulators (NAMs) Based on Functionalized Pyrazolo[1,5- a]pyrimidine-5-carboxamide and Thieno[3,2- b]pyridine-5-carboxamide Cores.基于功能化吡唑并[1,5-a]嘧啶-5-甲酰胺和噻吩并[3,2-b]吡啶-5-甲酰胺核心的新型中枢神经系统穿透性代谢型谷氨酸受体亚型 2（mGlu）负变构调节剂（NAMs）的发现。
J Med Chem. 2019 Jan 10;62(1):378-384. doi: 10.1021/acs.jmedchem.8b01266. Epub 2018 Oct 31.
9
Synergy between L-DOPA and a novel positive allosteric modulator of metabotropic glutamate receptor 4: implications for Parkinson's disease treatment and dyskinesia.L-DOPA 与代谢型谷氨酸受体 4 的新型正变构调节剂的协同作用：对帕金森病治疗和运动障碍的影响。
Neuropharmacology. 2013 Mar;66:158-69. doi: 10.1016/j.neuropharm.2012.03.022. Epub 2012 Apr 3.
10
4-aryl piperazine and piperidine amides as novel mGluR5 positive allosteric modulators.4-芳基哌嗪和哌啶酰胺类新型 mGluR5 正变构调节剂。
Bioorg Med Chem Lett. 2010 Dec 15;20(24):7381-4. doi: 10.1016/j.bmcl.2010.10.036. Epub 2010 Oct 21.

引用本文的文献

1
Advances and Insights in Positron Emission Tomography Tracers for Metabotropic Glutamate Receptor 4 Imaging.正电子发射断层扫描示踪剂在代谢型谷氨酸受体 4 成像中的研究进展与展望。
J Med Chem. 2024 Jul 11;67(13):10517-10529. doi: 10.1021/acs.jmedchem.3c02431. Epub 2024 Jun 26.
2
Experimental and theoretical comprehension of ESIPT fluorophores based on a 2-(2'-hydroxyphenyl)-3,3'-dimethylindole (HDMI) scaffold.基于2-(2'-羟基苯基)-3,3'-二甲基吲哚(HDMI)支架的激发态质子转移荧光团的实验与理论理解
Chem Sci. 2024 Apr 16;15(19):7206-7218. doi: 10.1039/d4sc01937g. eCollection 2024 May 15.
3
binding affinity prediction for metabotropic glutamate receptors using both endpoint free energy methods and a machine learning-based scoring function.
使用终点自由能方法和基于机器学习的评分函数预测代谢型谷氨酸受体的结合亲和力。
Phys Chem Chem Phys. 2022 Aug 3;24(30):18291-18305. doi: 10.1039/d2cp01727j.
4
New 1,2,4-oxadiazole derivatives with positive mGlu receptor modulation activity and antipsychotic-like properties.具有正代谢型谷氨酸受体调制活性和抗精神病特性的新型 1,2,4-恶二唑衍生物。
J Enzyme Inhib Med Chem. 2022 Dec;37(1):211-225. doi: 10.1080/14756366.2021.1998022.
5
Putative mGluR4 positive allosteric modulators activate G-independent anti-inflammatory mechanisms in microglia.假定的 mGluR4 正变构调节剂在小胶质细胞中激活 G 蛋白非依赖性抗炎机制。
Neurochem Int. 2020 Sep;138:104770. doi: 10.1016/j.neuint.2020.104770. Epub 2020 May 23.
6
Discovery of VU2957 (Valiglurax): An mGlu Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson's Disease.VU2957（瓦利格鲁拉克）的发现：一种代谢型谷氨酸受体正向变构调节剂，作为治疗帕金森病的临床前候选药物进行评估。
ACS Med Chem Lett. 2018 Oct 16;10(3):255-260. doi: 10.1021/acsmedchemlett.8b00426. eCollection 2019 Mar 14.