Caleb A. Jones, Renn A. Duncan, Kristen Gilliland, Carson W. Reed, Daniel H. Haymer, Paul K. Spearing, Rory A. Capstick, Bartholomew P. Roland, Paige Vinson, Marc Quitalig, Caroline Baggeroer, Natasha B. Billard, Jonathan W. Dickerson, Zixiu Xiang, Valerie M. Kramlinger, Olivier Boutaud, Julia Schlichtiger, Carrie K. Jones, Colleen M. Niswender, Hyekyung P. Cho, Jerri L. Rook, Carsten T. Wotjak, Matthias Freiwald, Riccardo Giovannini, Heiko Sommer, Scott Hobson, P. Jeffrey Conn, Bruce J. Melancon, Craig W. Lindsley
Abstract Herein, we report the discovery and development of the first-in-class (FIC), selective, and centrally active metabotropic glutamate receptor subtype 3 (mGlu3) positive allosteric modulator (PAM), VU6053371/BI03738809. A high-throughput screening campaign identified a potent and selective mGlu3 PAM VU6048261/DI013166572 based on a tetra-substituted thiophene core but with poor DMPK properties. Chemical lead optimization efforts managed to dramatically improve protein binding and in vivo rat PK to afford VU6053371/BI03738809. With an FIC in vivo tool compound, VU6053371/BI03738809 demonstrated robust efficacy in rat novel object recognition (NOR) (minimum effective dose (MED) = 3 mg/kg PO) and a clear pharmacokinetic/pharmacodynamic (PK/PD) relationship (PD efficacy observed when free brain concentrations were at, or above, the rat mGlu3 EC50). Thus, selective activation of mGlu3 represents a novel mechanism to address the cognitive impairment associated with schizophrenia (CIAS) and other neurodegenerative diseases. Moreover, the discovery of VU6053371/BI03738809 completes the group II mGlu receptor toolkit of in vivo PAM and NAM probes for both mGlu2 and mGlu3.