Discovery of VU6052959/BI’7927: A Selective mGlu ₃ Positive Allosteric Modulator (PAM) from an Orthogonal Benzoxazine Chemotype

Caleb A. H. Jones; Renn A. Duncan; Kristen Gilliland; Daniel H. Haymer; Paul K. Spearing; Rory A. Capstick; Bartholomew P. Roland; Paige Vinson; Marc Quitalig; Caroline Baggeroer; Natasha B. Billard; Jonathan W. Dickerson; Katherine J. Watson; Valerie M. Kramlinger; Olivier Boutaud; Daniel Ursu; Carsten T. Wotjak; Henning Priepke; Michel Garneau; Kristina Trenz; Colleen M. Niswender; Hyekyung P. Cho; Jerri M. Rook; Matthias Freiwald; Riccardo Giovannini; Heiko Sommer; Scott Hobson; P. Jeffrey Conn; Bruce J. Melancon; Craig W. Lindsley; Carson W. Reed

doi:10.1021/acsmedchemlett.6c00318

Key Points

This research aims to identify new positive allosteric modulators for the metabotropic glutamate receptor subtype 3 (mGlu3).
Conducted a high-throughput screening campaign to identify selective mGlu3 PAMs.
Optimized the lead compound VU6046180/BI’3690 to improve pharmacokinetic parameters.
Tested efficacy in a rat novel object recognition task.
VU6052959/BI’7927 was developed as a selective mGlu3 PAM based on the benzoxazine core.
Demonstrated efficacy in a rat model indicating potential cognitive benefits.
The compound's progression was halted due to the identification of a problematic Ames positive metabolite.

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Implication

Study discovers VU6052959/BI’7927 as a selective mGlu3 positive allosteric modulator, indicating potential therapeutic use.

Abstract

High Resolution Image Download MS PowerPoint Slide We report the discovery of an additional selective metabotropic glutamate receptor subtype 3 (mGlu 3 ) positive allosteric modulator (PAM) tool compound, VU6052959/BI’7927. A high-throughput screening (HTS) campaign identified a selective mGlu 3 PAM VU6046180/BI’3690 ( 7 ) containing a benzoxazine core (an orthogonal chemotype to previously reported thiophene tool compound VU6053371/BI’8809 ( 6 )). Lead optimization efforts focused on improving PK parameters led to the identification of VU6052959/BI’7927 ( 8 ). Orthogonal PAM 8 demonstrated efficacy in a rat novel object recognition task with conservation of our previously determined PK/PD relationship. However, an Ames positive metabolite halted further progression of 8 .

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Jones et al. (2026) studied this question.

synapsesocial.com/papers/6a4f39a72b81a944af574590 https://doi.org/10.1021/acsmedchemlett.6c00318

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Discovery of VU6052959/BI’7927: A Selective mGlu ₃ Positive Allosteric Modulator (PAM) from an Orthogonal Benzoxazine Chemotype

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Cite This Study

Discovery of VU6052959/BI’7927: A Selective mGlu ₃ Positive Allosteric Modulator (PAM) from an Orthogonal Benzoxazine Chemotype

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