Discovery of VU6005649, a CNS Penetrant mGlu7/8 Receptor PAM Derived from a Series of Pyrazolo[1,5-a]pyrimidines

被引：30

作者：

Abe, Masahito ^{[1
,2
]}

Seto, Mabel ^{[1
,2
]}

Gogliotti, Rocco G. ^{[1
,2
]}

Loch, Matthew T. ^{[1
,2
]}

Bollinger, Katrina A. ^{[2
]}

Chang, Sichen ^{[2
]}

Engelberg, Eileen M. ^{[1
,2
]}

Luscombe, Vincent B. ^{[1
,2
]}

Harp, Joel M. ^{[3
]}

Bubser, Michael ^{[1
,2
]}

Engers, Darren W. ^{[1
,2
]}

Jones, Carrie K. ^{[1
,2
,4
]}

Rodricuez, Alice L. ^{[1
,2
]}

Blobaum, Anna L. ^{[1
,2
]}

Conn, P. Jeffrey ^{[1
,2
,4
]}

Niswender, Colleen M. ^{[1
,2
,4
]}

Lindsley, Craig W. ^{[1
,2
,4
]}

机构：

[1] Vanderbilt Univ, Dept Pharmacol, Sch Med, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Sch Med, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Dept Biochem, Sch Med, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Med Ctr, Vanderbilt Kennedy Ctr, Nashville, TN 37232 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2017年 / 8卷 / 10期

关键词：

Positive allosteric modulator (PAM); metabotropic glutamate receptor 7 (mGlu(7)); cognition; VU6005649; Rett syndrome; WORKING-MEMORY; GRM7; GENE; ASSOCIATION; METHYLPHENIDATE; SCHIZOPHRENIA; EXTINCTION; CHILDREN; DEFICITS;

D O I：

10.1021/acsmedchemlett.7b00317

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein, we report the structure-activity relationships within a series of mGlu(7) PAMs based on a pyrazolo[1,5-c]pyrimidine core with excellent CNS penetration (K(p)s > 1 and K-p,K-uu,s > 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.

引用

页码：1110 / 1115

页数：6

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