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

作者：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; Rodricuez Alice L; Blobaum Anna L; Conn P Jeffrey; Niswender Colleen M^*; Lindsley Craig W^*

来源：ACS Medicinal Chemistry Letters, 2017, 8(10): 1110-1115.

DOI：10.1021/acsmedchemlett.7b00317

• Positive allosteric modulator (PAM)
• metabotropic glutamate receptor 7 (mGlu(7))
• cognition
• VU6005649
• Rett syndrome

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.

• 出版日期2017-10