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

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

Herein, we report the structure-activity relationships within a series of mGlu PAMs based on a pyrazolo[1,5- ]pyrimidine core with excellent CNS penetration ( s > 1 and s > 1). Analogues in this series proved to display a range of Group III mGlu receptor selectivity, but VU6005649 emerged as t...

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Veröffentlicht in:ACS medicinal chemistry letters 2017-10, Vol.8 (10), p.1110-1115
Hauptverfasser: Abe, Masahito, Seto, Mabel, Gogliotti, Rocco G, Loch, Matthew T, Bollinger, Katrina A, Chang, Sichen, Engelberg, Eileen M, Luscombe, Vincent B, Harp, Joel M, Bubser, Michael, Engers, Darren W, Jones, Carrie K, Rodriguez, Alice L, Blobaum, Anna L, Conn, P Jeffrey, Niswender, Colleen M, Lindsley, Craig W
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Sprache:eng
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Zusammenfassung:Herein, we report the structure-activity relationships within a series of mGlu PAMs based on a pyrazolo[1,5- ]pyrimidine core with excellent CNS penetration ( s > 1 and 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 PAM, filling a void in the Group III mGlu receptor PAM toolbox and demonstrating efficacy in a mouse contextual fear conditioning model.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.7b00317