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Discovery of VU6005649, a CNS Penetrant mGlu 7/8 Receptor PAM Derived from a Series of Pyrazolo[1,5- a ]pyrimidines.

Authors :
Abe M
Seto M
Gogliotti RG
Loch MT
Bollinger KA
Chang S
Engelberg EM
Luscombe VB
Harp JM
Bubser M
Engers DW
Jones CK
Rodriguez AL
Blobaum AL
Conn PJ
Niswender CM
Lindsley CW
Source :
ACS medicinal chemistry letters [ACS Med Chem Lett] 2017 Sep 01; Vol. 8 (10), pp. 1110-1115. Date of Electronic Publication: 2017 Sep 01 (Print Publication: 2017).
Publication Year :
2017

Abstract

Herein, we report the structure-activity relationships within a series of mGlu <subscript>7</subscript> PAMs based on a pyrazolo[1,5- a ]pyrimidine core with excellent CNS penetration ( K <subscript>p</subscript> s > 1 and K <subscript>p,uu</subscript> 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 <subscript>7/8</subscript> PAM, filling a void in the Group III mGlu receptor PAM toolbox and demonstrating in vivo efficacy in a mouse contextual fear conditioning model.

Details

Language :
English
ISSN :
1948-5875
Volume :
8
Issue :
10
Database :
MEDLINE
Journal :
ACS medicinal chemistry letters
Publication Type :
Academic Journal
Accession number :
29057060
Full Text :
https://doi.org/10.1021/acsmedchemlett.7b00317