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

Masahito Abe; Mabel Seto; Rocco G Gogliotti; Matthew T Loch; Katrina A Bollinger; Sichen Chang; Eileen M Engelberg; Vincent B Luscombe; Joel M Harp; Michael Bubser; Darren W Engers; Carrie K Jones; Alice L Rodriguez; Anna L Blobaum; P Jeffrey Conn; Colleen M Niswender; Craig W Lindsley

doi:10.1021/acsmedchemlett.7b00317

Discovery of VU6005649, a CNS Penetrant mGlu_7/8 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. eCollection 2017 Oct 12.

Authors

Masahito Abe^{1

2}, Mabel Seto^{1

2}, Rocco G Gogliotti^{1

2}, Matthew T Loch^{1

2}, Katrina A Bollinger², Sichen Chang², Eileen M Engelberg^{1

2}, Vincent B Luscombe^{1

2}, Joel M Harp³, 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.

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.

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

Abstract

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