Discovery of VU6027459: A First-in-Class Selective and CNS Penetrant mGlu(7) Positive Allosteric Modulator Tool Compound

Reed Carson W.; Kalbfleisch Jacob J.; Wong Madison J.; Washecheck Jordan P.; Hunter Ashton; Rodriguez Alice L.; Blobaum Anna L.; Conn P. Jeffrey; Niswender Colleen M.; Lindsley Craig W.

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Discovery of VU6027459: A First-in-Class Selective and CNS Penetrant mGlu(7) Positive Allosteric Modulator Tool Compound

机译：Discovery VU6027459：一流的选择性和CNS渗透Mglu（7）正变形调节剂工具化合物

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Herein, we report the discovery of the first selective and CNS penetrant mGlu(7) PAM (VU6027459) derived from a "molecular switch" within a selective mGlu(7) NAM chemotype. VU6027459 displayed CNS penetration in both mice (K-p = 2.74) and rats (K-p = 4.78), it was orally bioavailable in rats (%F = 69.5), and undesired activity at DAT was ablated.

机译：在此，我们报告了从选择性Mglu（7）Nam趋化型的“分子开关”中衍生自“分子开关”的第一选择性和CNS渗透MGLU（7）PAM（VU6027459）的发现。 VU6027459在小鼠（K-P = 2.74）和大鼠（K-P = 4.78）中显示CNS渗透，在大鼠（％F = 69.5）中是口服生物的，并且DAT的不期望的活性被烧蚀。

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来源
《ACS medicinal chemistry letters》 |2020年第9期|共7页
作者
Reed Carson W.; Kalbfleisch Jacob J.; Wong Madison J.; Washecheck Jordan P.; Hunter Ashton; Rodriguez Alice L.; Blobaum Anna L.; Conn P. Jeffrey; Niswender Colleen M.; Lindsley Craig W.;
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作者单位

Vanderbilt Univ Dept Chem Nashville TN 37232 USA;

Vanderbilt Univ Dept Chem Nashville TN 37232 USA;

Vanderbilt Univ Dept Chem Nashville TN 37232 USA;

Vanderbilt Univ Dept Chem Nashville TN 37232 USA;

Vanderbilt Univ Warren Ctr Neurosci Drug Discovery Sch Med Nashville TN 37232 USA;

Vanderbilt Univ Warren Ctr Neurosci Drug Discovery Sch Med Nashville TN 37232 USA;

Vanderbilt Univ Warren Ctr Neurosci Drug Discovery Sch Med Nashville TN 37232 USA;

Vanderbilt Univ Warren Ctr Neurosci Drug Discovery Sch Med Nashville TN 37232 USA;

Vanderbilt Univ Warren Ctr Neurosci Drug Discovery Sch Med Nashville TN 37232 USA;

Vanderbilt Univ Dept Chem Nashville TN 37232 USA;

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正文语种 eng
中图分类药学;化学;
关键词
Metabotropic glutamate receptor; mGlu(7); positive allosteric modulator (PAM); VU6027459; Rett syndrome;

机译：代谢谷氨酸受体;mglu（7）;阳性变构调制器（PAM）;VU6027459;RETT综合征;

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1. Discovery of VU6027459: A First-in-Class Selective and CNS Penetrant mGlu(7) Positive Allosteric Modulator Tool Compound [J] . Reed Carson W., Kalbfleisch Jacob J., Wong Madison J., ACS medicinal chemistry letters . 2020,第9期

机译：Discovery VU6027459：一流的选择性和CNS渗透Mglu（7）正变形调节剂工具化合物
2. Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu3 selective and CNS penetrant negative allosteric modulator (NAM) [J] . Wenthur C.J., Morrison R., Felts A.S., Journal of Medicinal Chemistry . 2013,第12期

机译：发现（R）-（2-氟-4-（（-4-甲氧基苯基）乙炔基）苯基）（3-羟基哌啶-1-基）甲酮（ML337），一种mGlu3选择性和CNS渗透性负变构调节剂（NAM）
3. Development of Novel, CNS Penetrant Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1 (mGlu(1)), Based on an N-(3-Chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide Scaffold, That Potentiate Wild Type and Mutant mGlu(1) Receptors Found in Schizophrenics [J] . Garcia-Barrantes Pedro M., Cho Hyekyung P., Niswender Colleen M., Journal of Medicinal Chemistry . 2015,第20期

机译：基于N-（3-氯-4-（1,3-二氧代异吲哚-2-基）苯基）-3的新型代谢型谷氨酸受体亚型（mGlu（1））的中枢神经系统渗透性正变构调节剂的开发。 -甲基呋喃-2-羧酰胺支架，可增强精神分裂症患者的野生型和突变型mGlu（1）受体
4. IDENTIFICATION OF NADPH-INDEPENDENT GSH CONJUGATES OF ACETYLENE-CONTAINING POSITIVE ALLOSTERIC MODULATORS OF METABOTROPIC GLUTAMATE RECEPTOR SUBTYPE 5 [C] . Xiaoliang Zhuo, Xiaohua Huang, Andrew Degnan, ASMS Conference on Mass Spectrometry and Allied Topics . 2014

机译：鉴定含乙炔谷氨酸受体亚型5的含乙炔的阳性变构调节剂的NADPH-无关的GSH缀合物
5. Characterization of Novel α2/α3 Subtype-Selective GABAA Receptor Positive Allosteric Modulators [D] . Lewter, Lakeisha A. 2019

机译：新型α2/α3亚型选择性GABAA受体正变构调节剂的表征
6. Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337) an mGlu3 Selective and CNS Penetrant Negative Allosteric Modulator (NAM) [O] . Cody J. Wenthur, Ryan Morrison, Andrew S. Felts, -1

机译：发现（R）-（2-氟-4-（（-4-甲氧基苯基）乙炔基）苯基）（3-羟基哌啶-1-基）甲酮（ML337）一种mGlu3选择性和CNS渗透性负变构调节剂（NAM）
7. Development of Novel, CNS Penetrant Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1 (mGlu1), Based on an N-(3-Chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide Scaffold, That Potentiate Wild Type and Mutant mGlu1 Receptors Found in Schizophrenics [O] . Pedro M. Garcia-Barrantes, Hyekyung P. Cho, Colleen M. Niswender, 2015

机译：基于N-（3-氯-4-（1,3-二氧化硅吲哚啉-2-基）苯基）-3-甲基呋喃 - 基于N-（3-氯-4-（1,3-二氧化硅胺-2-基） - 3-甲基呋喃 - 2-甲酰胺支架，具有精神分裂症中的增强野生型和突变体MGLU1受体

Discovery of VU6027459: A First-in-Class Selective and CNS Penetrant mGlu(7) Positive Allosteric Modulator Tool Compound

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