Caleb A Jones, Renn A Duncan, Kristen M 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
We report the discovery of an additional selective metabotropic glutamate receptor subtype 3 (mGlu3) positive allosteric modulator (PAM) tool compound, VU6052959/BI'7927. A high-throughput screening (HTS) campaign identified a selective mGlu3 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.