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
  • 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).
Products