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

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

  • ACS Med Chem Lett. 2017 Sep 1;8(10):1110-1115. doi: 10.1021/acsmedchemlett.7b00317.
Masahito Abe 1 2,  Mabel Seto 1 2,  Rocco G Gogliotti 1 2,  Matthew T Loch 1 2,  Katrina A Bollinger 2,  Sichen Chang 2,  Eileen M Engelberg 1 2,  Vincent B Luscombe 1 2,  Joel M Harp 3,  Michael Bubser 1 2,  Darren W Engers 1 2,  Carrie K Jones 1 2 4,  Alice L Rodriguez 1 2,  Anna L Blobaum 1 2,  P Jeffrey Conn 1 2 4,  Colleen M Niswender 1 2 4,  Craig W Lindsley 1 2 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 2 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 3 Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 4 Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
PMID: 29057060 DOI: 10.1021/acsmedchemlett.7b00317
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 (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 mouse contextual fear conditioning model.

Keywords

Positive allosteric modulator (PAM); Rett syndrome; VU6005649; cognition; metabotropic glutamate receptor 7 (mGlu7).

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