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更新于：2025-05-07

VU6005649

更新于：2025-05-07

概要

概要

基本信息

药物类型

小分子化药

别名-

靶点

mGluR7 x mGluR8

作用方式

调节剂

作用机制

mGluR7调节剂(代谢型谷氨酸受体-7调节剂)、mGluR8 调节剂(glutamate metabotropic receptor 8 modulators)

治疗领域-

在研适应症-

非在研适应症-

原研机构

Vanderbilt University

在研机构-

非在研机构

Vanderbilt University

权益机构-

最高研发阶段无进展临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构/序列

分子式C16H12F5N3O

InChIKeyNYBZCKAQIIPSDS-UHFFFAOYSA-N

CAS号2137047-43-7

关联

100 项与 VU6005649 相关的临床结果

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100 项与 VU6005649 相关的转化医学

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100 项与 VU6005649 相关的专利（医药）

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项与 VU6005649 相关的文献（医药）

2017-12-14·ACS Medicinal Chemistry Letters3区 · 医学

VU6010608, a Novel mGlu₇ NAM from a Series of N-(2-(1H-1,2,4-Triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamides

3区 · 医学

Article

作者: Loch, Matthew T ; Rook, Jerri M ; Remke, Daniel H ; Niswender, Colleen M ; Engelberg, Eileen M ; Blobaum, Anna L ; Engers, Darren W ; Conn, P Jeffrey ; Roenfanz, Hanna F ; Lindsley, Craig W ; Rodriguez, Alice L ; McGowan, Kevin M ; Luscombe, Vincent B ; Spearing, Paul K ; Reed, Carson W ; Stansley, Branden J

Herein, we report the structure-activity relationships within a series of mGlu₇ NAMs based on an N-(2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamide core with excellent CNS penetration (K_p 1.9-5.8 and K_p,uu 0.4-1.4). Analogues in this series displayed steep SAR. Of these, VU6010608 (11a) emerged with robust efficacy in blocking high frequency stimulated long-term potentiation in electrophysiology studies.

2017-10-12·ACS Medicinal Chemistry Letters3区 · 医学

Discovery of VU6005649, a CNS Penetrant mGlu_7/8 Receptor PAM Derived from a Series of Pyrazolo[1,5-a]pyrimidines

3区 · 医学

Article

作者: Jones, Carrie K. ; Harp, Joel M. ; Conn, P. Jeffrey ; Luscombe, Vincent B. ; Engers, Darren W. ; Gogliotti, Rocco G. ; Loch, Matthew T. ; Blobaum, Anna L. ; Seto, Mabel ; Bollinger, Katrina A. ; Lindsley, Craig W. ; Niswender, Colleen M. ; Chang, Sichen ; Engelberg, Eileen M. ; Bubser, Michael ; Abe, Masahito ; Rodriguez, Alice L.

Herein, we report the structure-activity relationships within a series of mGlu₇ PAMs based on a pyrazolo[1,5-a]pyrimidine core with excellent CNS penetration (K_ps > 1 and K_p,uus > 1). Analogues in this series proved to display a range of Group III mGlu receptor selectivity, but VU6005649 emerged as the first dual mGlu_7/8 PAM, filling a void in the Group III mGlu receptor PAM toolbox and demonstrating in vivo efficacy in a mouse contextual fear conditioning model.

Nature Communications

Structural basis of positive allosteric modulation of metabotropic glutamate receptor activation and internalization

Article

作者: Gilliland, Kristen ; Salas-Estrada, Leslie ; Meyerson, Joel ; Kristt, Melanie ; Selvakumar, Purushotham ; Marx, Dagan C ; Abreu, Nohely ; Melancon, Bruce J ; Lee, Joon ; Levitz, Joshua ; Filizola, Marta ; Gonzalez-Hernandez, Alberto J ; Strauss, Alexa ; Huynh, Kevin ; Arefin, Anisul

The metabotropic glutamate receptors (mGluRs) are neuromodulatory family C G protein coupled receptors which assemble as dimers and allosterically couple extracellular ligand binding domains (LBDs) to transmembrane domains (TMDs) to drive intracellular signaling. Pharmacologically, mGluRs can be targeted at the LBDs by glutamate and synthetic orthosteric compounds or at the TMDs by allosteric modulators. Despite the potential of allosteric compounds as therapeutics, an understanding of the functional and structural basis of their effects is limited. Here we use multiple approaches to dissect the functional and structural effects of orthosteric versus allosteric ligands. We find, using electrophysiological and live cell imaging assays, that both agonists and positive allosteric modulators (PAMs) can drive activation and internalization of group II and III mGluRs. The effects of PAMs are pleiotropic, boosting the maximal response to orthosteric agonists and serving independently as internalization-biased agonists across mGluR subtypes. Motivated by this and intersubunit FRET analyses, we determine cryo-electron microscopy structures of mGluR3 in the presence of either an agonist or antagonist alone or in combination with a PAM. These structures reveal PAM-driven re-shaping of intra- and inter-subunit conformations and provide evidence for a rolling TMD dimer interface activation pathway that controls G protein and beta-arrestin coupling.

100 项与 VU6005649 相关的药物交易

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