Discovery of VU6053371/BI03738809: A First-in-Class Selective and CNS-Penetrant mGlu₃ Positive Allosteric Modulator...

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.