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Discovery of VU6053371/BI03738809: A First-in-Class Selective and CNS-Penetrant mGlu Positive Allosteric Modulator (PAM) with Efficacy in a Preclinical Cognition Model

Authors

Jones CA Caleb A , Duncan RA Renn A , Gilliland KM Kristen M , Reed CW Carson W , Haymer DH Daniel H , Spearing PK Paul K , Capstick RA Rory A , Roland BP Bartholomew P , Vinson P Paige , Quitalig M Marc , Baggeroer C Caroline , Billard NB Natasha B , Dickerson JW Jonathan W , Xiang Z Zixiu , Kramlinger VM Valerie M , Boutaud O Olivier , Schlichtiger J Julia , Jones CK Carrie K , Niswender CM Colleen M , Cho HP Hyekyung P , Rook JL Jerri L , Wotjak CT Carsten T , Freiwald M Matthias , Giovannini R Riccardo , Sommer H Heiko , Hobson S Scott , Conn PJ P Jeffrey , Melancon BJ Bruce J , Lindsley CW Craig W .
ACS chemical neuroscience. 2026 06 06; 17(12).
2406-2418

Abstract

Herein, we report the discovery and development of the first-in-class (FIC), selective, and centrally active metabotropic glutamate receptor subtype 3 (mGlu) positive allosteric modulator (PAM), VU6053371/BI03738809. A high-throughput screening campaign identified a potent and selective mGlu 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 rat PK to afford VU6053371/BI03738809. With an FIC 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 mGlu EC). Thus, selective activation of mGlu 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 PAM and NAM probes for both mGlu and mGlu.