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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.

ABSTRACT: 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.

SUBMITTER: Abe M

PROVIDER: S-EPMC5641958 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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

Abe Masahito M Seto Mabel M Gogliotti Rocco G RG Loch Matthew T MT Bollinger Katrina A KA Chang Sichen S Engelberg Eileen M EM Luscombe Vincent B VB Harp Joel M JM Bubser Michael M Engers Darren W DW Jones Carrie K CK Rodriguez Alice L AL Blobaum Anna L AL Conn P Jeffrey PJ Niswender Colleen M CM Lindsley Craig W CW

ACS medicinal chemistry letters 20170901 10

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 (Kps > 1 and Kp,uus > 1). Analogues in this series proved to display a range of Group III mGlu receptor selectivity, but VU6005649 emerged as the first dual mGlu7/8 PAM, filling a void in the Group III mGlu receptor PAM toolbox and demonstrating in vivo efficacy in a mo ...[more]

PMID: 29057060

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